DE69707497T2 - BENZOPYRANOPYRROLE AND BENZOPYRANOPYRIDINE WITH ALPHA-1 ADRENERGIC EFFECT - Google Patents

Abstract

The present invention relates to a compound of formula (I) and the pharmaceutically acceptable salts thereof wherein W is a bicyclic heterocyclic ring system. The compounds are alpha -1 adrenergic antagonists and are useful in the treatment of BPH; also disclosed are alpha -1 antagonist compositions and a method for antagonizing alpha -1 adrenoreceptors and treating BPH.

Description

1. Technical field

The present invention relates to novel organic compounds and compositions which are alpha-1 (α-1) adrenoreceptor antagonists, processes for preparing such compounds, synthetic intermediates used in these processes, and a method for inhibiting α-1 adrenoreceptors and for treating benign prostatic hyperplasia (BPH) or other urological diseases such as bladder outlet obstruction and neurogenic bladder, or gynecological syndromes such as dysmenorrhea.

2. Background of the invention

Adrenergic neurons play a major role in the innervation of the heart, blood vessels, and smooth muscle tissue. Compounds capable of interacting with adrenoreceptor sites within adrenergic nerves can induce a variety of physiological responses, including vasoconstriction, vasodilation, and decreased or increased heart rate (chronotropy), contractility (inotropy), and metabolic activity. In the past, various adrenergic compounds have been used to influence these and other physiological responses. However, many adrenergic compounds do not possess sufficient selectivity to enable desired actions with adrenergic adrenoreceptor sites. That is, these adrenergic Compounds do not demonstrate a high degree of specificity for the different adrenoreceptor types within the adrenergic neurons to produce a desired physiological response that is distinct from other possible and possibly less desirable responses of the system.

Benign prostatic hyperplasia (BPH) is a condition that develops in middle-aged and older men and refers to the benign overgrowth of the stromal and epithelial elements of the prostate that is associated with aging. Symptoms of BPH include increased micturition frequency, nocturia, weak urine stream, and hesitancy or delay in initiating urine flow. The chronic consequences of BPH may include hypertrophy of the bladder smooth muscle, decompensated bladder, and increased incidence of urinary tract infection.

BPH usually begins in the mid-fifties and is the most common cause of urinary tract problems in men of this age. BPH is apparently rare in men before the age of 40, but by age 60, approximately 50% of men have histologic evidence of BPH. The prevalence of BPH continues to increase with age until by age 80, approximately 80% of men have pathologic evidence of BPH.

Although prostatic hyperplasia is a common finding in older men, the appearance of urinary symptoms is the main feature that distinguishes simple anatomical enlargement of the prostate from prostatism, which is the clinical syndrome in which the patient perceives significant obstruction of urinary flow. It is not uncommon for older men to have a palpably enlarged prostate without showing the signs of prostatism. From the patient's perspective, however, the appearance and progression of urinary symptoms is more important than the mere presence of an enlarged prostate.

The discovery of large numbers of alpha-adrenergic adrenoreceptors in the smooth muscle of the prostate capsule and bladder neck in the 1970s (M. Caine, et ah, Brit. J. Urol., 47: 193-202 (1975)) concluded that there is both a static and a dynamic component to the bladder outflow obstruction associated with BPH. The static component arises with aging from progressive hyperplasia of the prostate, which leads to narrowing of the urethra, causing the symptoms of urinary tract obstruction. Superimposed on this essentially mechanical problem is the varying degree of smooth muscle contraction, which is controlled by the sympathetic nervous system and influenced by factors such as stress, cold, and sympathomimetic drugs. It is this dynamic component that explains the often rapid fluctuations in symptoms observed in patients with prostate disease.

The most effective treatment for BPH currently is the surgical procedure of transurethral resection of the prostate (TURP). Since it removes the obstructing tissue (Chromatography. Chapple, Br. Med. Journal 304: 1198-1199 (1992)), it is the treatment that addresses both the static and dynamic components of BPH. However, this surgical treatment is associated with mortality rates (1%) and adverse events (incontinence 2-4%, infection 5-10%, and impotence 5-10%). A noninvasive alternative treatment procedure would therefore be highly desirable.

The incidental clinical observation that urinary tract incontinence occurred in women during antihypertensive treatment with prazosin (T. Thien, KP Delacre, FMJ Debruyne, RAP Koene, Br. Med. Journal, 622-623 (1978)) and the experimental work of Caine (cited above) led to the recognition of the possible role of selective α-1 adrenoreceptor blockade in lower urinary tract disease. Subsequent studies by various groups have documented the functional role of α-1 adrenoreceptors compared to α-2 adrenoreceptors in the stromal portion of the prostate, thus suggesting a possible molecular basis for the use of specific α-1 adrenoreceptor blockers in the non-surgical treatment of BPH (Chromatography. R. Chapple, ML Aubry, S. James, M. Greengrass, G. Burnstock, RT Turner-Warwick, Br. J. Urol. 63: 487-496 (1989)). The clinical efficacy of α-1 antagonists in BPH has been demonstrated with various non-selective α-1 blockers, including terazosin (Hytrin®), prazosin and doxazosin. Treatment periods as short as two to four weeks with α-1 adrenoreceptor blockers showed objective improvements in mean and peak HR flow velocities (14-96%) with subjective improvements in patient symptom scores (RA Janknegt, CR Chapple, Eur. Urol. 24: 319-326 (1993)). Long-term studies with terazosin, indoramin, prazosin and doxazosin have shown similarly significant improvements in urinary flow rates and subjective symptom scores (RA Janknegt, cited above, H. Lepor, G. Knapp-Maloney, J. Urol. 145: 263A (1991), W. Chow, D. Hahn, D. Sandhu, Br. J. Urol. 65: 36-38 (1990) and CR Chapple, TJ Christmas, EJG Milroy, Urol. Int. 45: 47-55 (1990)). However, these agents have similar dose-limiting effects: hypotension, dizziness and muscle weakness.

In recent years it has become clear that BPH and bladder outflow obstruction (BOG) are clinically distinguishable and that the severity of clinical BPH is related to several factors in addition to BOO (Lepor, H., Alpha Blockade for the Treatment of Benign Prostatic Hyperplasia, Urol. Clin. N. Amer., 22: 375-386, 1995). For example, BOO may be associated with other urological symptoms such as detrusor instability (Rosier, PFWM, JJMCH de la Rosette, H. Wijkstra, Ph.EV Van Kerrebroeck and FMJ Debruyne, 1 s Detrusor Instability in Elderly Males Related to the Grade of Obstruction?, Neurourol. Urodynam., 14: 625-633, 1995). In addition, the role of extraprostatic α-1 adrenoreceptors has been found to be important in the etiology of lower urinary tract symptoms, so that antagonism of these receptors in the spinal cord, ganglia, aer nerve endings, urinary bladder and bladder neck or external urethral sphincter may be important in the drug treatment of urological conditions such as BOO and neurogenic bladder (Andersson, KE., Prostatic and extraprostatic α- adrenoceptors-Contributions to the Lower Urinary Tract Symptoms in Benian Prostatic Hyperplasia, Scand. J. Urol, and Nephrol., 30: 105-111, 1996). The recognition that women possess paraurethral glands that have anatomical, histological, and biochemical similarities to the male prostate (Gittes, RF and RM Nakamura, Female urethral syndrome: A female prostatitis?, Western J. Medicine, 164: 435-438, 1996) suggests a possible role for α-1 adrenoreceptor antagonists as a drug treatment to improve some of the symptoms of female urethral symptoms. In addition, α-adrenoreceptors are functionally important for uterine smooth muscle contraction (Miller, MD and JM Marshall, Uterine response to nerve stimulation: relation to hormonal status and catecholamines, Am. J. Physiol., 209: 859-863, 1965), and modulation of the sympathetic response to catecholamines is enhanced by increases in estrogen levels (Miller and Marshall, Uterine response to nerve stimulation: relation to hormonal status and catecholamines, Am. J. Physiol., 209: 859- 863, 1965). Consistent with this observation are data showing increasing levels of α-adrenoreceptor responses and receptor density following estrogen administration to animals (Hoffman, Ex. B., TN Lavin, RJ Lefkowitz, and RR Ruffolo, Jr., Alpha adrenergic receptor subtypes in rabbit uterus: Mediation of myometrial contraction and regulation by estroaens, J. Pharmacol. Exp. Ther., 219: 290-295, 1981 and Roberts, JM, PA Insel, and A. Goldfein, Repulation of myometrial adrenoreceptors and adrenergic response by sex steroids, Mol. Pharmacol., 20: 52-58, 1981). Thus, hormonal regulation of α-1 adrenoreceptor sensitivity may play a role in increased uterine contractions in dysmenorrhea, a condition for which selective α-1 Adrenoreceptor antagonists may offer therapeutic potential.

Thus, there is a need for a "uroselective" α-1 antagonist with reduced probabilities for side effects.

Summary of the invention

In its main embodiment, the present invention provides certain benzopyranopyrrole and benzopyranopyridine compounds and intermediates according to formula I:

or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of 2 to 10 carbon atoms, and R₃ is selected from the group consisting of,

wherein G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl,

Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent, and if Y' is oxygen or sulfur, G' is absent,

V and V' are independently selected from the group consisting of nitrogen and methine, and U is a ring attached to its adjacent ring and selected from the group consisting of (a) an unsubstituted or substituted five-membered ring having five carbon atoms; (b) an unsubstituted or substituted five-membered ring having four carbon atoms and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (c) an unsubstituted or substituted five-membered Ring having three carbon atoms and two heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; (d) a substituted or unsubstituted six-membered ring having six carbon atoms; (e) a substituted or unsubstituted six-membered ring having five carbon atoms and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (f) a substituted or unsubstituted six-membered ring having four carbon atoms and two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and (g) a substituted or unsubstituted six-membered ring having three carbon atoms and three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The five-membered rings constituting U can contain 0, 1 or 2 double bonds. The six-membered rings constituting U can contain 0, 1, 2 or 3 double bonds. The rings (a)-(g) of the group constituting U may be mono- or di-substituted with substituents independently selected from the group consisting of alkyl, alkoxy, cyano, nitro, carboxy, alkoxycarbonyl of two to eight carbon atoms, halogen, cycloalkyl, aryl and heterocycle.

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound according to formula I in association with a pharmaceutically effective carrier.

The present invention also relates to a method for antagonizing α-1 adrenoreceptor binding in a host mammal, particularly a human, by administering a therapeutically effective amount of a composition comprising a compound according to formula I. In particular, the present invention relates to a method for treating BPH in a mammal, particularly a human, by administering to a mammal an effective amount of a compound according to formula I.

Detailed description of the invention

In one embodiment, the present invention provides a compound according to formula I

or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of 2 to 10 carbon atoms and R₃ is selected from the group consisting of,

wherein G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl,

Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G' is absent,

V and V' are independently selected from the group consisting of nitrogen and methine, and U is a ring attached to its adjacent ring and selected from the group consisting of (a) an unsubstituted or substituted five-membered ring having five carbon atoms; (b) an unsubstituted or substituted five-membered ring having four carbon atoms and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (c) an unsubstituted or substituted five-membered ring having three carbon atoms and two heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, (d) a substituted or unsubstituted six-membered ring having six carbon atoms; (e) a substituted or unsubstituted six-membered ring having five carbon atoms and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (f) a substituted or unsubstituted six-membered ring having four carbon atoms and two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and (g) a substituted or unsubstituted six-membered ring having three carbon atoms and three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The five-membered rings constituting U may contain 0, 1 or 2 double bonds. The six-membered rings constituting U may contain 0, 1, 2 or 3 double bonds. The rings (a)-(g) of the group constituting U may be mono- or di-substituted with substituents independently selected from the group consisting of alkyl, alkoxy, cyano, nitro, carboxy, alkoxycarbonyl of two to eight carbon atoms, halogen, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a preferred embodiment, the present invention provides a compound according to formula II:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl,

Y and Y' are independently chosen from the group consisting of oxygen, nitrogen and sulphur, provided that if Y is oxygen or sulphur, G is absent, and if Y' is oxygen or sulphur, G' is absent,

P', Q, S' and T are independently selected from the group consisting of nitrogen and methine, provided that no more than two of P', Q, S' and T can be nitrogen, and R4 and R5 are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocycle; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula III:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of. hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G' is absent, P' and T are nitrogen, Q and S' are methine and R4 and R5 are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl or heterocycle; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention a compound according to formula IV:

wherein R₁ and R₂; are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1, or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl, and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G' is absent, P' is nitrogen, Q, S' and T are methine, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula V:

wherein R₁ and R₂ are independently selected from the group consisting of selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino, and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl, and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen, and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G' is absent, Q is nitrogen, P', S', and T are methine, and R4 and R5 are methyl, methyl, ethyl, ethyl, propyl, butyl ... are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula VI:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, with the proviso that if Y is oxygen or is sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, S' is nitrogen, P', Q and T are methine, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula VII:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G' is absent, T is nitrogen, P', Q and S' are methine, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula VIII:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl, and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, among which. provided that if Y is oxygen or sulfur, G is absent and if Y' is oxygen or sulfur, G' is absent, P', Q, S' and T are methine, and R4 and R5 are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula IX:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 1, W is a Alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, P', Q, S' are methine, T is nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula X:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 2, W is an alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, P', Q and S' are methine, T is nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula XI:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 2, W is a Alkylene of 2 to 10 carbon atoms, is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, Q and S' are methine, P' and T are nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula XII:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 1, W is an alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, Q and S' are methine, P' and T are nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula XIII:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 1, W is a Alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, Q, S' and T are methine, P' is nitrogen and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof.

In a further preferred embodiment, the present invention provides a compound according to formula XIV:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, Y is nitrogen, G is hydrogen, Y' is sulfur, P' and T are nitrogen, Q is methine, and S' is carbon; or a pharmaceutically acceptable salt, ester or prodrug thereof.

The present invention also relates to compounds or salts thereof which are useful as intermediates of structural formulas I-XIV. A compound which is useful as an intermediate is a compound according to formula XV:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, and n is 1 or 0.

Another compound which is useful as an intermediate is a compound according to formula XVI:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, and n is 1 or 0.

Another compound which is useful as an intermediate is a compound according to formula XVII:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, m is from 2 to 10 and n is 1 or 0.

A more preferred compound useful as an intermediate is a compound according to formula XVIII:

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, and n is 1 or 0. In addition, a more preferred compound according to Formula XVII is one having an absolute stereochemistry which is 3aR and 9bR.

Another preferred compound useful as an intermediate is a compound according to formula XIX:

wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, and n is 1 or 0. In addition, a more preferred compound according to formula XIX is one having an absolute stereochemistry which is 3aR and 9bR.

Another preferred compound useful as an intermediate is a compound according to formula XX:

wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, m is from 2 to 10, and n is 1 or 0. Additionally, a more preferred compound according to Formula XX is one having an absolute stereochemistry which is 3aR and 9bR.

Another compound which is useful as an intermediate is a compound according to formula XXI:

where U, Y', G' are as defined in formulas I-XIV and R is alkyl.

Another compound which is useful as an intermediate is a compound according to formula XXII:

wherein U, Y', G' are as in formulas I-XIV and R is alkyl.

Another compound which is useful as an intermediate is a compound according to formula XXIII:

where U, Y', G' and m are as defined in formulas I-XIV and R is alkyl.

Another compound which is useful as an intermediate is a compound according to formula XXIV:

XXIV, wherein Rz is alkyl.

Another compound which is useful as an intermediate is a compound according to formula XXV:

XXV, wherein Rz is alkyl.

Another compound which is useful as an intermediate is a compound according to formula XXVI:

XXVI, wherein X is a halogen and R is selected from alkyl and arylalkyl.

Another compound which is useful as an intermediate is a compound according to formula XXVII:

Another compound which is useful as an intermediate is a compound according to formula XXVIII:

Another compound which is useful as an intermediate is a compound according to formula XXIX:

The present invention also relates to a process for preparing a compound according to the formula

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R₁, R₂, A, n, W, Y, G, Y', G', P, Q, S, T, R₄ and R₅ are as previously defined; and which comprises the steps:

a) the reaction of a compound according to formula

where Ra is aminoalkyl,

b) with a compound according to the formula

where R is alkyl.

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound according to structural formulas I-XIV in combination with a pharmaceutically acceptable carrier.

The invention further relates to a method for Antagonizing α-1 adrenoreceptors in a host mammal, particularly a human, in need of such treatment by administering a therapeutically effective amount of a compound according to formulas I-XIV.

The invention further relates to a method for treating BPH in a host mammal, in particular in a human, in need of such treatment by administering a therapeutically effective amount of a compound according to formulas I-XIV.

The invention further relates to a method for treating bladder outlet obstruction (BOO) in a host mammal, particularly humans, in need of such treatment by administering a therapeutically effective amount of a compound according to formulas I-XIV.

The invention further relates to a method for treating neurogenic bladder weakness in host mammals, particularly in humans, who require such treatment, by administering a therapeutically effective amount of a compound according to formulas I-XIV.

The invention further relates to a method for treating uterine smooth muscle contraction in female host mammals, particularly humans, in need of such treatment by administering a therapeutically effective amount of a compound according to formulas I-XIV.

As used within this specification and in the appended claims, the following terms have the following meanings:

The term "alkenyl" as used herein refers to a hydrocarbon containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl, and the like.

The terms "alkyl" or "lower alkyl" as used herein refers to straight or branched chain alkyl radicals comprising 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n- Propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "alkylamino" as used herein refers to R₁₀NH- wherein R₁₀ is an alkyl group, for example, ethylamino, butylamino and the like.

The term "alkylene" means a divalent group derived from a straight or branched chain saturated hydrocarbon of 2 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene and the like.

The term "alkoxy" as used herein refers to R₁₁O- wherein R₁₁ is an alkyl group as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, tert-butoxy, and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group as defined herein attached to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

The term "alkoxyalkoxy" refers to R₁₂O-R₁₃O- wherein R₁₂ is alkyl and R₁₃ is alkylene. Examples of alkoxyalkoxy include methoxymethoxy, methoxyethoxy, and the like.

The term "alkoxycarbonyl" as used herein refers to R14O-C(O)- wherein R14 is an alkyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like.

The term "alkylsulfonyl" refers to R₁₅S(O)₂- wherein R₁₅ is an alkyl group.

The term "alkynyl" refers to a straight or branched chain hydrocarbon containing a carbon-carbon triple bond. Examples of alkynyl include -C C-, -C C-CH₂-, -C C-CH(CH₃)-, and the like.

The term "amino" as used herein means -NH₂.

The term "aminoalkyl" as used herein refers to an alkyl radical to which an amino group (-NH₂) is attached.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups may be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, nitro, carboxy, alkoxycarbonyl, and carboxamide.

The term "arylalkyl" as used herein refers to an aryl attached to the parent moiety via an alkyl radical.

The term "carboxamide" as used herein refers to -C(O)NH₂ wherein the carboxylic acid hydroxy moiety has been replaced by an amine.

The term "carboxyalkyl" as used herein refers to a carboxy group (-C(O)OH) attached to an alkyl radical as previously defined. Examples of carboxyalkyl include carboxymethyl, carboxyethyl, and the like.

The term "cyanoalkyl" as used herein refers to a cyano group (-CN) attached to the parent moiety via an alkyl radical.

The term "dialkylamino" as used herein refers to R16R17N- wherein R16 and R17 are independently alkyl, for example, diethylamino, methylpropylamino, and the like.

The term "carboxy" as used herein refers to a carboxylic acid radical, -C(O)OH.

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like. Cycloalkyl groups may be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, haloalkyl, alkoxy, thioalkyloxy, Amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

The term "halogen" or "halo" as used herein means I, Br, Cl or F.

The term "haloalkyl" as used herein refers to a lower alkyl radical as defined above which bears at least one halogen substituent, for example chloromethyl, fluoroethyl or trifluoromethyl and the like.

The terms "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refer to any 3- or four-membered ring containing one heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from oxygen, nitrogen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring has from 0-3 double bonds. The nitrogen heteroatoms may optionally be quaternized. The term "heterocyclic" also includes bicyclic groups in which one of the above heterocyclic rings is fused to a benzene ring or to a cyclohexane ring or other heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like). Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl; Piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, and benzothienyl.

Heterocycles may be unsubstituted or monosubstituted or di-substituted with substituents independently selected from hydroxy, halo, oxo (=O), alkylimino (R₁₈N= where R₁₈ is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, Arylalkyl, -COOH, -SO₃H and lower alkyl. In addition, nitrogen-containing heterocycles can be N-protected.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group as defined above attached to a lower alkyl radical as defined above.

The term "hydroxy" as used herein means -OH.

The term "hydroxyalkyl" as used herein refers to an alkyl radical attached to a hydroxy group.

The term "methine" as used herein means -CH=.

The term "nitro" as used herein means -NO₂.

The term "thioalkoxy" as used herein refers to R₁₉S- wherein R₁₉ is alkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and the like.

By "pharmaceutically acceptable salt" is meant those salts which, within the consideration of reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and which are consistent with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharm. Sciences, 66: 1-19 (1977). The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts can be prepared in situ, during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with an appropriate organic acid. These salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, Cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. The basic nitrogen-containing groups can also be quaternized with such active ingredients as alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others. Water or oil soluble or dispersible products are thus obtained.

Examples of acids which can be used to form pharmaceutically acceptable acidic addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula I or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other typical inorganic amines which are useful are suitable for the formation of basic additional salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The term "pharmaceutically acceptable ester" as used herein refers to esters which hydrolyze in vivo and includes those which are rapidly broken down in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedionic acids, in which each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates.

The term "pharmaceutically acceptable prodrug" as used herein refers to those prodrugs of the compounds of the present invention which, within the consideration of reasonable medical judgment, are suitable for use in contact with the tissues of humans or lower animals without undesirable toxicity, irritation, allergic response and the like, consistent with a reasonable benefit/risk ratio and effective for their intended use, as well as the zwitterionic forms, if possible, of the compounds of the invention. The term "prodrug" refers to compounds which are rapidly converted in vivo to yield the parent substance having the above structural formula, for example by hydrolysis in blood. An in-depth review is available in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Volume 14 of A. C. S. Symposium Series and in Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmacuetical Associaton and Pergamon Press, 1987.

As used throughout this specification and in the appended claims, the term metabolically separable group refers to a moiety which is readily separated in vivo from the compound bearing it, said compound remaining pharmacologically active after separation or Metabolically severable groups constitute a class of groups which are reactive with the carboxyl group of the compounds of this invention and are well known to those skilled in the art. They include, but are not limited to, groups such as alkanoyl, such as acetyl, propionyl, butyryl, and the like; unsubstituted and substituted aroyl, such as benzoyl and substituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl; trialkylsilyl, such as trimethyl- and triethylsilyl; monoesters formed with dicarboxylic acids, such as succinyl, and the like. Due to the ease with which the metabolically severable groups of the compounds of this invention can be separated in vivo, the compounds bearing such groups act as prodrugs of α-1 adrenoreceptor antagonist compounds. The compounds bearing the metabolically separable groups have the advantage of exhibiting improved bioavailability as a result of the improved solubility and/or improved absorption rate imparted to the parent compound by the presence of the metabolically separable group.

Compounds of the present invention include compounds resulting from non-natural or synthetic preparations, including in vitro and in situ preparations or as a result of in vivo production, e.g., in vivo metabolism.

Asymmetric centers may be present in the compounds of the present invention. The present invention encompasses the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the present invention are prepared by synthesis from starting materials containing the chiral centers or by the preparation of mixtures of enantiomeric products followed by separation, such as by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques or by direct separation of the optical enantiomer on chiral chromatographic columns. The starting materials of certain Stereochemistry are either commercially available or are prepared by the methods detailed below and resolved by techniques well known in the art of organic chemistry. Typical compounds falling within the scope of Formula I include:

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thienxo[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bS)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-methoxy-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-1-(2-Methoxyethyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-methoxypyrido[2',3':4,5]thierio[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidln-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[5-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) pentyl]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[5-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) pentyl]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(2H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-2,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-2,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(2H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione;

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3a5,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-methoxypyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-chloropyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenyipyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-isopropoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahycito-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano(3,4-c]pyrrol-2-yl) butyl)-8-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-MethoXy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[2',3':4,5)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((BaR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2';3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3a5,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-berizopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-furyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-cis-7-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[3-((±)-cis-7-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[3-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-cis-6-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[3-((±)-cis-6-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl]-[1] benzothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-pyrido[2 ',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-trans-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-pyrido[2 ',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydto-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyranol[3,4-c]pyrrol-2-yl)butyl] - pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[3-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] -6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione,

3-[4-((±)-trans-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-6,7 -dimethoxy-quinazoline-2,4(1H,3H)-dione,

3-[4-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-6,7 -dimethoxy-quinazoline-2,4(1H,3H)-dione,

3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] -6,7-dimethoxy-quinazoline2,4(1H,3H)-dione,

3-[3-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrand[3,4-c]pyrido-3-yl) propyl]-6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione,

3-[3-((±)-trans-10-methoxy-2,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) propyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione,

3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

3-[3-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) propyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) ethyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione,

3-[2-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) ethyl]-6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione,

3-[3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[3-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-28-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-(-cis-7-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dioh,

3-[4-((3aR,9bR)-cis-6-Hydroxy-9-methoxy-1,2,3,3a,4,9bhexahydro-[1]-benzopyrano[3,4-c]pyrrole-2- yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(2-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, and

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-B-(4-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Preferred compounds falling within the scope of formula (I) include:

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1)-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]- benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-chloro-, pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H, 3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(2H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-isopropoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyriido-3- yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidln-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-furyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-(cis-7-Hydroxy-9-Methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] -8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-6-Hydroxy-9-methoxy-1,2,3,3a,4,9bhexahydro-[1]-benzopyrano[3,4-c]pyrrole-2- yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-didn,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(2-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, and

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(4-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt, ester or prodrug thereof.

The following compounds can be prepared by procedures described in the synthetic schemes and examples contained herein:

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2,3-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,4-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4,3-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrdl-2-yl) butyl]-pyrido[3,2-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,4-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,2-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2,3-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrtol-2-yl) butyl]-pyrido[3,4-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,2-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4,3-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-benz[g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-benz[h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-benz[f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2,3-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2,3-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[3,4-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[4,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,5- f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[3,4- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,3- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,5- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[3,4- h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,3- h]quinazoline-2,4(18,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,5- h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[4,5-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[5,4-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[4,5- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[5,4- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[4,5- h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[5,4- h]quinazolih-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2,3-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydto-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,4-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4,3-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,2-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,4-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,2-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2,3-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,4-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3,2-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4,3-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-benz[g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-benz[h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-benz[f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2,3-g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopytano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2,3-h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[3,4- f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,3-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,5- f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[3,4- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,3- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,5- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[3,4- h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,3- h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridazino[4,5- h]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[4,5-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[5,4-f]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[4,5- g]chlnazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[5,4- g]quinazoline-2,4(1H,3H)-dione,

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-ollpyrrol-2-yl)butyl] -pyrimidino[4,5- h]quinazoline-2,4(1H,3H)-dione, and

3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrimidino[5,4- h]quinazoline-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Typical compounds of the present invention were evaluated for their ability to displace prazosin from its adrenoreceptor.

In vitro binding assays

In the following, for the purpose of discussing alpha-1 adrenoreceptor subtypes, the IUPHAR convention of using lowercase letters to define molecular clones and uppercase letters to indicate pharmacologically defined adrenoreceptors was used. Otherwise, the recently recommended nomenclature for alpha-1 (α1a, α1b, α1d) was used.

Typical compounds of the invention were evaluated for α-adrenoreceptor binding affinity in vitro using [3H]-prazosin as radioligand and three cloned α-1 adrenoreceptors expressed in LTK cells: α-1a (bovine), α-1b (hamster), and α-1d (rat). In addition, binding affinity against the pharmacologically defined α-1A adrenoreceptor (rat submaxillary gland) was measured.

The cDNA clones encoding the α-1 adrenoreceptors (α-1a, α-1b, and α-1d) were purchased from TULCO (Triangle Universities Licensing Consortium, Research Triangle Park, NC) and inserted into the eukaryotic expression vector SnaB30. In this vector, expression of the adrenoreceptor gene is under the transcriptional control of an SV40 early promoter. Positive drug selection is ensured by a neomycin resistance gene. Mouse fibroblast cells (LTK) were transfected with the α1 expression plasmids and grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum and 30uM G418. Stable G418 resistant strains were generated and successful expression of adrenoreceptor protein was monitored using radioligand binding techniques. The stable single cell clones derived from the strains were examined in adrenoreceptor binding assays to identify those clones that had high adrenoreceptor density. Roller bottle cultures of the cloned strains were used to provide cell membranes for the following adrenoreceptor binding characterization studies. A cell line containing the SnaB30 vector expressing the human erythropoietin gene served as a negative control.

For the adrenoreceptor binding assays, large-scale membrane preparations were used in which 6 million cells were seeded into small (450 cm2) Corning tissue culture roller bottles. 200 ml of DMEM containing 10% fetal calf serum and 30 µM G418 was added to each roller bottle. A 95% air/5% CO2 gas mixture (sterile) was introduced into each roller bottle prior to sealing. The bottles were then incubated at 37ºC on a roller rack for 5 days. Cells were re-fed with fresh medium after three days in culture.

On the fifth day of culture, growth medium was removed from cells grown in roller bottles, and cells were washed twice with PBS (Sigma, 120 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4-NaH2PO4, pH = 7.4). Cells were detached from roller bottles by incubation for 15 minutes at 37°C in a Tris-EDTA solution (10 mM Tris, 100 mM NaCl, 1 mM EDTA, pH = 7.4). The cell suspension from each roller bottle was decanted into checkered centrifuge tubes and stored on ice. An aliquot of each cell suspension was taken for cell counting in bulk. Cells were centrifuged at 3000 x G for 5 minutes at 2-4°C, washed with PBS, and centrifuged again. The supernatant was decanted and the pellet weighed to determine the wet weight of the cells. The cells were washed one final time in 40 volumes of 5 mM Tris-HCl, 5 mN EDTA, pH = 7.7, and centrifuged at 40,000 x G for 10 minutes. The cells were homogenized in 10 ml of 50 mM Tris-HCl, 5 mM EDTA (pH = 7.4) and diluted in 40 ml/tube. The homogenates were centrifuged at 40,000 x G for 10 minutes. The supernatant was decanted and the pellets were again homogenized in 50 mM Tris-HCl (pH = 7.4) and centrifuged as before. The supernatant was decanted and the homogenate was resuspended in 6.25 volumes (per gram wet weight) of 50 mM Tris-HCl and aliquots of the pooled homogenates were frozen in liquid N2 and stored at -70°C until the time of assay. Rat submaxillary glands were used as α-1A adrenoreceptors and were prepared essentially as described in (Michel, AD, Loury, DN and Whiting, RL, Brit. J. Pharmacol. 98: 83-889 (1989)).

The receptor binding assays for α-1 adrenoreceptors were performed essentially as described by Greengrass and Bremner (Eur. J. Pharmacol. 55: 323-326 (1979)). Briefly, Plastic BioblocksTM (DBM Scientific, Valencia, CA) were incubated at 25ºC for 50 minutes with 500 uL of membrane homogenar (diluted with an additional 96 volumes [for cloned adrenoreceptors, 12 volumes for submaxillary glands] in 50 mN Tris-HCl buffer (pH = 7.7 at the time of assay), 450 uL of [3H]prazosin (0.2 nM final concentration, 75-85 Ci/mmol, DuPont-NEN Corp., Boston, MA) and 50 uL of either water (for total binding) or 10 uM phentolamine (final concentration, for non-specific binding). After equilibration, the recovered radioligand was separated from the free on GF/B filters (soaked in 0.5% polyethyleneimine) using either a Brandel or Packard cell harvester. Radioactivity was detected by standard liquid scintillation techniques. Data were analyzed as previously described (Hancock, A. A., Kyncl, J. J., Martin, Y. C., and Dessernardis, J. F., J. Receptor Res. 8: 23-46 (1988)).

Dog prostate strips were used in vitro as previously described (Hieble, J. P., Boyce, A. J., and Caine, M., Fed. Proc., 45: 2609-2614 (1986)) to demonstrate antagonistic abilities against phenylephrine-induced contractions.

The results are shown in Table 1. The results demonstrate that the compounds of the invention bind to the α-1 adrenoreceptor and exhibit varying degrees of specificity for the α-1a adrenoreceptor. Table 1 In vitro data for binding to α-1 adrenoreceptors

Functional antagonism at α-1 adrenoreceptors

Functional assays indicative of pharmacologically defined α-1 adrenoreceptors were used to further characterize the compounds. Inhibition of phenylephrine (PE)-induced contraction of canine prostatic smooth muscle can be correlated with α-1A adrenoreceptor activation. Inhibition of PE-induced contraction of rat spleen is indicative of α-1B adrenoreceptor antagonism and inhibition of PE-induced contraction of rat vas deferens correlates with α-1A adrenoreceptor antagonism (RP Burt, CR Chapple and I Marshall, Er. J. Pharmacoi. 107: P324 (1992)). For each of these models, agonist dose response curves were repeated against increasing concentrations of test drug to derive a Schild plot [log (EC₅₀-1) against log (molarity of test substance)] to determine pA2. Data for prazosin, terazosin and doxazosin show a greater effect on splenic smooth muscle of approximately one order of magnitude.

Canine prostate strips were used in vitro as previously described (Hieble, J. P., Boyce, A. J., and Caine, M., Fed. Proc., 45: 2609-2614 (1986)) to demonstrate antagonist activities against phenylephrine-induced contractions.

The results are shown in Table 2. The results show that the compounds of the invention exhibit functional antagonism of α-1 adrenoreceptors. Table 2 In vitro data for functional antagonism of α-1 adrenoreceptors

In vivo determination of intraurethral pressure (IUP) in dogs

The intraurethral pressure (IUP) model in aged dogs is an accepted model of measuring the effect of prostatic smooth muscle contraction on urethral tone. Dogs also have an enclosed prostate covering the urethral sac, thus providing an anatomical correlate with humans.

Beagle dogs (Marshall Farms) older than 2 years and weighing between 12 and 15 kg were pre-anesthetized with thiopental sodium 15 mg/kg i.v. (PentothalTM, Abbott) and then placed under general anesthesia (isoflurane). A 7F Swan-Ganz balloon catheter (Multiflex - list no. 41224-01 Abbott) was lubricated with a water-soluble gel, inserted into the urethral opening and advanced approximately 40 cm in male dogs (significantly less in females) until the balloon tip was well within the urinary bladder. The balloon was then inflated with 1 ml of room air and the catheter was slowly pulled through until just past the first resistance felt at the bladder neck. Previous experiments in which dogs were sacrificed after such placement confirmed that this technique results in reliable positioning of the balloon within the prostatic urethra in the appropriate position in females. The balloon port of the catheter was connected to a Gould Stathani P23Dd pressure transducer, which was linked to a computer-controlled data acquisition system (Modular Instruments, Inc., Malvern, PA) for measuring intraurethral pressure (IUP).

The dogs were then treated with propranolol to reduce the β- Adrenoreceptor agonist effects of the test agonists. Dose-response curves of the intraurethral pressor effect of epinephrine (EPI) were obtained before and after each of up to 3 increasing doses of a test antagonist (iv). After each antagonist dose, 15 minutes were allowed for equilibration before the next agonist dose response was initiated. The increase in IUP induced by a given agonist dose was allowed to return to baseline before the next dose was administered. The estimated antagonist dissociation constant (in vivo pseudo pA2) was determined by Schild analysis (Brune, et al., Drug Development Research, 34: 267-275 (1995)).

The results are shown in Table 3. The results demonstrate that the compounds of the invention inhibit EPI-induced increases in IUP.

Table 3 Inhibition of EPI-induced increase in IUP in dogs In vivo characterization (pseudo pA2) Example No. IUD

13 8.61

26 8.22

39 8.10

67 6.70

Prazosin 7.88

Prazosin 6.91

Terazosin 6.90

Spontaneous hypertensive rat (SHR) model

The SHR has historically been used as a predictor of the hypotensive effects of α-1 adrenoreceptor antagonists. Male spontaneously hypertensive rats were anesthetized and the left femoral artery and vein characterized to measure of mean arterial pressure (MAP) or for drug administration. The arterial catheter was connected to a Gould Statham p23ID transducer and the pressure waveform was recorded. MAP (mm Hg) and heart rate (HR, beats/minute) were measured on-line using a BUXCO cardiovascular analyzer. After a 30 minute predose control period, each rat was given a dose of test antagonist iv and MAP and heart rate were monitored for an additional 2½ hours. The area under the hypertensive response curve up to 60 minutes post-dose (T₆₀ AUC) was determined using a trapezoidal rule integration of the percent change from the control arterial pressure data set. Results are expressed as pED₅₀ Values defined as the negative logarithm of the dose producing a hypotensive response of -1250, which represents 50% of the area under the curve between SHR and normotensive rats.

The results are shown in Table 4. The results show that the compounds of the invention are weakly hypotensive.

Table 4 Spontaneous hypertensive rat (SHR) assay In vivo characterization (pseudo pA2) Example No. SHR

13 6.15

26 6.4

39 5.2

67 4

97 5.9

Prazosin 7.4

Prazosin 6.59

Terazosin 6.74

Pharmaceutical compositions

The present invention also encompasses pharmaceutical compositions comprising compounds of the present invention together formulated with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically formulated for oral administration, in solid or liquid form for parenteral injection, or for rectal administration.

The pharmaceutical compositions of this invention can be administered to humans or other animals orally, rectally, parenterally, intracisternally, intraperitoneally, topically (such as by powder, ointments or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration as used herein refers to routes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

Pharmaceutical compositions of this invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions shortly before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Suitable fluidity can be achieved, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifiers or dispersing agents. The prevention of the action of microorganisms can be ensured are achieved by the inclusion of numerous antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include isotonic agents such as sugar, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases it is desirable to slow the absorption of the drug from a subcutaneous or intramuscular injection in order to prolong the action of the drug. This can be achieved by using a liquid dispersion of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug will then depend on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or dispersing the drug in an oily vehicle.

Injectable depot forms are prepared by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer used, the drug delivery rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which are dissolved or dispersed in sterile water or other sterile injectable media immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable binder or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silica, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as Example: cetyl alcohol and glycerol monostearate h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type can be used as fillers in soft and hard-filled gelatin capsules using such binders as, for example, lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms are tablets, dragees, capsules, pills and granules and can be manufactured with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may also comprise covering agents and may also be of such a composition that the active ingredients are concentrated only, or preferentially, in a particular part of the digestive tract. release, optionally in a delayed manner. Examples of surrounding compositions which may be used include polymeric substances and waxes.

The active compounds may also, if appropriate, be microencapsulated with one or more of the above-mentioned binders.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Apart from inert diluents, the oral compositions may also comprise excipients such as emulsifying and suspending agents, sweetening agents, flavoring and perfuming agents.

Suspensions may comprise, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating binders or carriers such as for example cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but become liquid at body temperature and therefore melt in the rectum and release the active compound.

Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic and physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound according to the present invention, stabilizers, preservatives, binders and the like. The preferred lipids are the phospholipids and the phosphatidylcholines (lecithins), both natural and synthetic.

Methods for forming liposomes are well known in the art. See, for example, Prescott, Ed., Methods in Cell Biolociy, Volume XIV, Academic Press, New York, N. Y. (1976), pp. 33 et seq.

Dosage forms for topical administration of a compound according to this invention include powders, sprays, ointments and inhalations. The active compound is admixed in sterile compositions with a pharmaceutically acceptable carrier and any required preservative powder or driving agent which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also within the scope of this invention.

The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied to achieve an amount of the active compound(s) effective to achieve the desired therapeutic response for a particular patient, composition, and route of administration. The usual dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and medical history of the patient being treated. However, it is within the skill of the art to begin with dosages of compounds at lower levels than those required to achieve the therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

Generally, dosage levels of from about 0.01 to about 50, preferably from about 0.05 to about 5 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four divided doses per day.

Methods for preparing the compounds of the invention are shown in Schemes 1-9. In the following Schemes, R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl. In the following Schemes, n = 1 or 2, m = 1-6, R = alkyl and Y, G, G', U and U' are as previously defined.

Scheme 1 shows the general procedure for the preparation of the compounds of this invention. The secondary amine 1 is constructed to the compounds of this invention (7) by one of two general procedures. Alkylation of 1 with a haloalkyl nitrile in the presence of a non-nucleophilic base such as ethyldiisopropylamine, K2CO3 or the like to generate an intermediate nitrile (2) which is then reduced using LiAlH4, AlH3, BH3 catalytic hydrogenation or the like generates the intermediate aminoalkyl substituted analogue 3. Treatment of this amine with a heterocyclic isocyanate of general formula 5 yields an intermediate urea which either spontaneously ring to the pyrimidinedione product 7 or does so under basic catalysis. Alternatively, if R is a component other than H, the carbamoyl chloride 6 produces the isocyanate 5. Alternatively, the secondary amine 1 can be used to react with the haloalkyl heterocyclic urea of general formula 4 in the presence of a non-nucleophilic base such as ethyldiisopropylamine, K₂CO₃ or the like to give the title compounds of the invention (7) directly.

The amine 1, where n = 1, is prepared as shown in Scheme 2 (for the cis ring fusion) and in Scheme 3 (for the trans ring fusion). For the cis-fused product, treatment of the appropriately substituted coumarin 8 with the azomethine ylide precursor N-trimethylsilylmethyl-N-methoxymethylbenzylamine 9 produces the ring-closed product 10 selectively as the cis isomer. Reduction of the lactone with LiAlH4, BH3, AH3, LiBH4, or the like gives the alcohol 11. Activation of the primary alcohol as a chloride 12, bromide, mesylate, or the like followed by treatment with a base such as KOtBu, NaOMe, NaOH, K2CO3 or the like results in ring closure to the cis-fused benzopyranopyrrole nucleus 13. Removal of the benzyl group from the amine, most conveniently accomplished by catalytic hydrogenation, gives the cis-fused secondary amine 14.

For the trans-fused product, treatment of the appropriately substituted trans-cinnamate 15 (Scheme 3) with the azomethine ylide precursor, N-trimethylsilylmethyl-N-methoxymethylbenzylamine 9, produces the ring-closed product 16 selectively as the trans isomer. Reduction of the ester with LiAlH4, BH3, AlH3 or the like followed by hydrolysis of the phenol protecting group gives the alcohol 17. Activation of the primary alcohol as a chloride 18, bromide, mesylate or the like followed by treatment with a base such as KOtBu, NaOMe, NaOH, K2CO3 or the like leads to the ring formation to the transfused benzopyranopyrrole nucleus 19. Removal of the benzyl group from amine, most conveniently achieved by catalytic hydrogenation, gives the transfused secondary amine 20.

In a preferred embodiment of this invention, substitution of the azomethine ylide precursor 21 derived from (R)-α-methylbenzylamine in place of 9 allows derived from benzylamine, the synthesis of the preferred (3aR, 9bR) amine 22 from 5-methoxycoumarin (Scheme 4), and the preferred (3a5, 9bR) amine 23 from ethyl 2-methoxy-6-methoxymethyl-trans-cinnamate (Scheme 5). In Scheme 4, the reagents PPh3/CCl4 can be replaced using methanesulfonyl chloride and triethylamine.

In another preferred embodiment of this invention, a precursor to a compound according to formula 1, where n = 2, (4aR, 10bS)-trans-10-methoxy-1,3,4,4a,5,10bhexahydro-2H-[1]-benzopyrano[3,4-c]pyridine (28) is prepared as shown in Scheme 6. The imide 24 is prepared from ethyl 2-methoxy-6-methoxymethylcinnamate and ethyl N-benzylamidomalonate according to the method of Faruk and Martin, U.S. Patent No. 4,902,801. Reduction with LiAlH4, AlH3, BH3 or the like followed by conversion of the primary alcohol to a suitable leaving group such as chloro, bromo, mesylate or the like; Hydrolysis of the protected phenol and intramolecular ring formation followed by debenzylation gives the racemic trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine 25. Reaction of the secondary amine with a chiral chloroformate, such as methyl chloroformate, gives a mixture of diastereomeric carbamates, which can then be separated chromatographically. Removal of the carbamate group by treatment with n-BuLi then gives the enantiomerically resolved secondary amine 28.

In a further preferred embodiment of the present invention, the compounds according to formula I-XIV and formula XXI-XXV can be prepared as shown in Scheme 7. Condensation of phenylglyoxal monooxime (30) with 2-aminomalononitrile tosylate salt (31) followed by reduction of the resulting pyrazine N-oxide (32) with triethyl phosphite, sodium bisulfite, triphenylphosphine or the like gives regioselectively 33. Diazotization of the amino functionality followed by replacement with CuBr, CuCl or the like gives the intermediate chloro- or bromopyrazine (34) which after base-controlled condensation with methyl thioglycolate gives the Thienopyrazine intermediate (35). Use of other alkyl thioglycolates such as ethyl, n-propyl, n-alkyl or substituted alkyls would yield alternative thienopyrazine intermediates having different alkyl groups on the ester. Allowing thienopyrazine intermediate (35) to react with phosgene, diphosgene, triphosgene or the like in the presence of an inert solvent produces the isocyanate (36) according to Formula XXV.

In another preferred embodiment of the present invention, a compound according to XV-XX is prepared according to the procedure depicted in Scheme 8. Activation of the free hydroxyl of (37) as a methanesulfonate, toluenesulfonate, benzenesulfonate or the like, or as a halide, followed by nucleophilic displacement with 2-bromo or 2-iodoresorcinol monomethyl ether gives the ether intermediate (40). The ether intermediate (40) where X = Br or I can be ring closed by forming the enolate of the lactam with a metal amide (such as KHMDS, LiHMDS, LDA, NaNH₂, KNH₂ or the like) and exposing it to a metal salt (Cu+, Cu2+, Mn2+, Fe2+, Fe3+ and the like) similarly to the work of McKillop (McKillop, J. Chem. Soc., Perkin Trans, I., 1993, 2433). Alternatively, a metal enolate of the lactam (40) can be exposed to a transition metal complex (such as Pd/C or Pd(PPh3)4) or a transition metal salt complex (salts of Pd2+ that cannot or can be complexed to phosphines, amines or nitriles) to produce compound (41) where R is an unsubstituted benzyl group. Deprotection of 41 can be achieved using catalytic hydrogenation conditions. Alkylation of 42 with a haloalkyl nitrile in the presence of a non-nucleophilic base, such as ethyldiisopropylamine, K2CO3, or the like, to give an intermediate nitrile (43), which is then reduced using LiAlH4, AlH3, BH3, catalytic hydrogenation, or the like, produces the intermediate aminoalkyl substituted analogue (44).

In a further embodiment of the present In accordance with the invention, a lactam intermediate can be prepared as shown in Scheme 9 by reacting 1-hydroxy-2-formaldehyde-3-methoxybenzene (45) in a protic solvent such as isopropyl alcohol or the like with a tertiary amine base such as DABCO or the like and methyl acrylate to produce the chromene (47). Condensation of the chromene with nitromethane in the presence of a non-nucleophilic base such as DBJ or potassium tert-butoxide or the like gives the intermediate nitroester (48) which is then reduced to the lactam (49) using catalytic hydrogenation and a base such as sodium methoxide or the like. Scheme 1 Scheme 2 Scheme 3 Scheme 4 Scheme 5 Scheme 6 Scheme 7 Scheme 7b Scheme 8 Scheme 9

The foregoing may be better understood by reference to the following examples, which are provided for illustration purposes and are not intended to limit the scope of the inventive concept.

The following abbreviations are used: K₂CO₃ for potassium carbonate, LiAlH₄ for lithium aluminium hydride, AlH₃ for aluminium hydrate, BH₃ for borane, BH₂·DMS for borane dimethyl sulfide complex, DABCO for 1,4-diazabicyclo[2.2.2]octane, DBU for 1,8-diazabicyclo[5.4.9]undec-7-ene, DMF for dimethylformamide, DMSO for dimethyl sulfoxide, Et₃N for triethylamine, Et₂O for diethyl ether, EtOAc for ethyl acetate, EtOH for ethanol, KotBu for potassium tert-butoxide, LDA for lithium diisopropylamide, MeOH for methanol, NaOMe for sodium methoxide, NaOH for sodium hydroxide, HCl for hydrochloric acid, H₂/Pd for hydrogen and a palladium catalyst, iPrOH for Isopropyl alcohol and THF for tetrahydrofuran, cat. TFA for catalytic trifluoroacetic acid, Pph3/CCl4 for triphenylphosphine/carbon tetrachloride and n-BuLi for n-butyllithium.

example 1 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 1A (3aR, 9bR)-cis-9-methoxy-2-(R)-α-methylbenzyl-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole -4-on

5-Methoxycoumarin (22.3 g, 126 mmol) and trifluoroacetic acid (0.97 mL, 12.6 mmol) were combined in CH2Cl2 (200 mL) and cooled to 0 °C. To the stirred solution was added N-methoxymethyl-Ntrimethylsilylmethyl-(R)-α-methylbenzylamine (63.4 g, 252 mmol) over 30 min. The reaction was stirred for an additional 30 min at 0 °C, and then for 1 h at 25 °C. The reaction mixture was washed with 5% NaHCO3, the organic layer was dried and evaporated. The resulting oil was suspended in diethyl ether and after 2 h the title compound was collected for filtration, (15.4 g, 38%). 1 H NMR (300 MHz, CDCl3 ) ? 1.36 (d, 3H), 2.41 (dd, 1H), 3.04 (d, 1H), 3.05-3.15 (m, 2H), 3.23 (m, 1H), 3.32 (1, 1H), 3.75 (m, 1H), 3.79 (s, 3H), 6.61 (d, 1H), 6.67 (d, 1H), 7.18 (t, 1H), 7.20- 7.35 (m, 5H).

Example 1B (3aR,9bR)-cis-9-methoxy-2-(R)-α-methylbenzyl-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The resulting product from Example 1A (15.3 g, 47 mmol) in THF (200 mL) was added to a suspension of LiAlH4 (3.6 g, 94 mol) in THF (200 mL) was added over 15 min. After 2 h at 25 °C, the reaction was quenched (Fieser workup) and the intermediate alcohol isolated by evaporation of the solvent. The alcohol (15.2 g, 46 mmol) was combined with triphenylphosphine (24.3 g, 93 mmol) in a 4:1 ratio of acetonitrile and CCl₄, and the resulting solution was heated to reflux for 1 h. The solvent was evaporated and the resulting product was isolated as a mixture of the title compound and an intermediate chlorophenol. The mixture was treated with 1 M potassium t-butoxide (12 mmol) in THF (50 mL). The solvent was evaporated and the product was partitioned between dil aq. NaOH and ethyl acetate. The organic layer was dried and evaporated to give, after chromatographic purification, 11.9 g (84%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.36 (d, 3H), 2.23-2.31 (m, 2H), 2.59 (m, 1H), 3.04 (dd, 1H), 3.20 (q, 1H), 3.23 (q, 1H), 3.38 (q, 1H), 3.77 (s, 3H), 3.81 (q, 1H), 4.01 (q, 1H), 6.41 (d, 1H), 6.52 (d, 1H), 7.04 (t, 1H), 7.20- 7.35 (m, 5H).

Example 1C (3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 13 (7.7 g, 24.9 mmol) was dissolved in methanol (300 mL) and palladium hydroxide on charcoal (1.5 g) was added. The reaction was stirred rapidly under one atmosphere of H2 for 18 hours. The reaction was filtered and evaporated to give the title compound (4.6 g, 90%): 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1 H), 6.55 (d, 1H), 7.17 (t, 1H); [α]D -95.7° (MeOH).

Example 1D (3aR, 9bR)-cis-2-(3-cyanopropyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 1C (7.0 g, 34 mmol) was combined with 4-bromobutyronitrile (5.6 g, 37.5 mmol) and ethyldiisopropylamine (8.9 mL, 51 mmol) in acetonitrile (50 mL) and the reaction was stirred at 80 °C for 4 h. The reaction was quenched in 5% aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were washed with brine, dried and evaporated. The resulting product was purified by column chromatography to give the title compound (7.5 g, 81%): 1H NMR (300 MHz, CDCl3) δ 1.82 (m, 2H), 2.30 (m, 2H), 2.43 (t, 2H), 2.45-2.65 (m, 3H), 3.04 (dd, 1H), 3.23-3.42 (m, 2H), 3.79 (dd, 1H), 3.82 (s, 3H), 4.06 (dd, 1H), 6 .46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).

Example 1E (3aR,9bR)-cis-2-(4-aminobutyl)-9-methoxy-1,2,3,3a,4,9bhexahydro-[1]-benzopyrano[3,4-c]pyrrole

LiAlH4 (7.8 g, 207 mmol) was suspended in THF (200 mL) and cooled to 0 °C. To the solution was added AlCl3 (9.2 g, 69 mmol) in small portions over 15 minutes. The product from Example 1D (7.5 g, 27.5 mmol) in THF (50 mL) was then added over 15 minutes and the reaction was allowed to warm to 25 °C and stirred for 1.5 hours. The reaction was quenched by the addition of 10.5 mL of H2O, 10.5 mL of 15% aqueous KOH, and 42 mL of H2O. The reaction was filtered through celite and the solvent evaporated to give the title compound (6.6 g, 87%): 1H NMR (300 MHz, CDCl3) δ 1.65-1.80 (m, 4H), 2.19 (m, 1H), 2.25 (dd, 1H), 2.42 (m, 1H), 2.52 (t, 2H), 3.14 (dd, 1H), 3.18-3.30 (m, 2H), 3.79 (dd, 1H), 3.80 (s, 3H), 4.04 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).

Example 1F 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate, prepared by the procedure described in J. Heterocyclic Chem., 24:85 (1987), (0.624 g, 3.00 mmol) and triethylamine (0.84 mL, 6.0 mmol) were dissolved in THF (20 mL) and to the solution was added 1.7 mL of a 1.93 M solution of phosgene in toluene (3.3 mmol). After 2 h, the product from Example 1E (0.78 g, 2.8 mmol) was added. After 4 h, the reaction was quenched in aqueous 5% NaHCO3 and extracted with CH2Cl2. The organic extracts were dried and evaporated. The resulting urea was dissolved in toluene (100 mL) and heated to reflux for 18 hours. The cooled reaction mixture was filtered and the resulting free base of the title compound was treated with anhydrous HCl in ethanol. Addition of diethyl ether resulted in crystallization of the title compound (0.76 g, 57%). mp 241-243º (dec); 1H NMR (300 MHz, CDCl3 (free base)) δ 1.56-1.99 (m, 2H), 1.71-1.83 (m, 2H), 2.26 (t, J = 9 Hz, 1H), 2.34 (dd, J = 6, 10 Hz, 1H), 2.50-2.70 (m, 3H), 3.26 (dd, J = 7, 10 Hz, 1H), 3.43 (q, J = 8 Hz, 1H), 3.63 (t, J = 8 Hz, 1H), 3.79 (s, 3H), 3.76-3.86 (m, 1H), 4.01 (dd, J = 4, 11Hz, 1H), 4.11 (t, J = 7 Hz, 1H), 6.43 (d, J = 8 Hz, 1H), 6.49 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 7.49 (dd, J = 4.8 Hz, 1H), 8.23 (dd, J = 1.8 Hz, 1H), 8.78 (dd, J = 1.4 Hz, 1H);

MS (DCI(NH3)) m/e 479 (M + H)+; Analysis calcd for C25H26N4O4S·HCl·(H2O)0.25: C, 57.80; H, 5.34; N, 10.78; Found: C, 57.72; H, 5.46; N, 10.58.

Example 1G

Alternative Synthesis of (3aR,9bR)-cis-2-(4-Aminobutyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

To a solution of 5-methoxycoumarin in THF at 15ºC was added Trifluoroacetic acid was added. To this was added a solution of N-methoxymethyl-N-trimethylsilylmethyl-(R)-α-methylbenzylamine in t-butyl methyl ether. After the addition was complete, the mixture was stirred at 25 °C for 1 h and then concentrated in vacuo. The residue was diluted with ethyl acetate, stirred at 5 °C for 1.5 h, and filtered. The filter cake was washed with ethyl acetate and dried to give (3aR,9bR)-cis-9-methoxy-2-(R)-α-methylbenzyl-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-4-one.

Lithium borohydride and tetrahydrofuran were combined and cooled to less than -10ºC. A solution of pyrrolidine lactone in tetrahydrofuran was slowly added while maintaining the temperature below 0ºC. The solution was stirred at about 5ºC for 1 hour and then distilled under vacuum. To the residue was added methanol and the contents were heated to reflux for 2 hours. A solution of ammonium chloride in water was added and the reaction mixture was distilled under vacuum at less than 55ºC. The residue was extracted with toluene and the toluene layer was washed with distilled water. The washed toluene layer was then distilled down under vacuum at less than 55ºC.

Tetrahydrofuran was added to the toluene and cooled to 0 ± 10ºC and triethylamine was added. Methanesulfonyl chloride in toluene was added and the mixture was stirred at 0 ± 10ºC for 1 hour. A solution of potassium t-butoxide in tetrahydrofuran was added and stirred below 10ºC for not less than 1 hour. Toluene was added and the layers were washed with ammonium chloride in water followed by the distilled water. A sample of the solution can then be concentrated in vacuo.

Alternatively, the material could be purified by concentrating in vacuo to an oil, adding isopropanol and then anhydrous hydrogen chloride in isopropanol. The solution was stirred for 3 hours at room temperature and the resulting slurry was filtered. The filter cake was washed with isopropanol and dried in an oven at 35 °C for 16 hours to give the hydrochloride salt (3aR,9bR)-cis-9-methoxy-2-(R)-α-methylbenzyl-1,2,3,3a,4,9b-hexahydro-[1]-berizopyrano[3,4-c]pyrrole.

To a solution of (3aR,9bR)-cis-9-methoxy-2-(R)-α- methylbenzyl-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4- c]pyrrole hydrochloride in ethanol was added 50% wet 5% palladium on carbon. The flask was purged with hydrogen and heated to 50 °C at 50 psi for 16 hours. The catalyst was filtered and the solvent removed under vacuum at ca. 40 °C to give the hydrochloride salt of (3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4- c]pyrrole.

The product from Example 1C (7.0 g, 34 mmol) was combined with 4-bromobutyronitrile (5.6 g, 37.5 mmol) and ethyldiisopropylamine (8.9 mL, 51 mmol) in acetonitrile (50 mL) and the reaction was stirred at 80 °C for 4 hours. The reaction was quenched in 5% aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were washed with brine, dried and evaporated. The resulting product was purified by column chromatography to give (3aR,9bR)-cis- 2-(3-cyanopropyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]- benzopyrano[3,4-c]pyrrole.

Alternatively to the procedure in Example 1E, a nitrogen purged hydrogenating agent was charged with Raney nickel and methanol. The slurry was stirred and allowed to sediment. The supernatant was removed via a dip tube. This was repeated a third and fourth time. The Raney nickel was then slurried with ethanol and a solution of the product of Example 1D in methanol was added. The internal temperature was cooled to about 0°C and ammonia was added. The hydrogenating agent was purged three times with hydrogen and the pressure increased to 50 psi. The solution was hydrogenated at 25°C for 2 hours. When the reaction was complete, the catalyst was filtered through a bed of Celite and the filter cake was washed with methanol. The combined filtrates were then placed in a another reactor and distilled under vacuum at less than 40°C to a residue. Toluene was added followed by the addition of sodium hydroxide in water. The biphasic solution was filtered through a pad of celite into another reactor and the layers were separated. The organic layers were washed with water and the toluene distilled under vacuum at less than 45°C to give the primary amine.

Example 1H Synthesis of compound 40 in Scheme 8

To a solution of water (500 mL) and itaconic acid (108.9 g, 0.83 mol) was added phenethylamine (101.4 g, 0.83 mol). This was heated under reflux for 24 hours, cooled to room temperature and the liquid decanted. The solid was then dissolved in 40% aqueous ethanol (800 mL) under reflux. The solution was slowly cooled to room temperature and filtered. The filter cake was washed with water (200 mL), twice with ethanol (200 mL) and dried to give 82.1 g of a white solid.

A solution of the white solid (82 g, 0.35 mol) in methanol (500 mL) was heated to reflux with trimethyl chloroformate (37.3 g, 0.35 mol) and sulfuric acid (ca. 0.5 g) for 16 hours. This was cooled to room temperature and sodium borohydride (26.48 g, 0.7 mol) was added portionwise. The solution was then heated to reflux for 2 hours, concentrated in vacuo to ca. 300 mL. The solution was evaporated with aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (once with 500 mL, three times with 300 mL). The combined organic layers were concentrated in vacuo to an oil (34 g) of compound (37), which was comparable to the previously reported compound (Domagala, J. Med. Chem., 1987, 30, 1711).

To a solution of alcohol, compound (37) (30 g, 0.137 mol) in THF (300 mL) was added triethylamine (13.84 g, 0.137 mol) followed by tosyl chloride (26.08 g, 0.137 mol). This was stirred for 14 hours at room temperature. The reaction was diluted with ethyl acetate (300 mL) and washed with 5% sodium bicarbonate (400 mL) and twice with 1% sodium bicarbonate (300 mL), dried over sodium sulfate and concentrated in vacuo to an oil of compound (38): 1HNMR (CDCl3) δ 7.78 (d, 2H, J = 8 Hz), 7.4-7.2 (m, 7H), 5.45 (q, 1H, J = 6.5 Hz), 4.0-3.9 (m, 2H), 3.1-3.0 (m, 2H), 2.65-2.5 (m, 1H), 2.4 (d, 1H, J = 12 Hz); 2.45 (s, 3H), 2.15-2.05 (m, 1H), 1.43 (d, 3H, J = 7 Hz).

To a solution of 3-methoxyphenol (100 g, 0.81 mol) in methylene chloride (500 mL) was added dihydropytane (184 mL, 2.01 mol) and pyridinium p-toluenesulfonate (10.1 g, 0.04 mol) at room temperature. This solution was stirred at room temperature for 5 h before quenching with saturated sodium bicarbonate (250 mL). The organics were separated and the aqueous layer extracted twice with methylene chloride (250 mL). The combined organics were then washed with saturated NaCl (250 mL), dried over sodium sulfate, and concentrated in vacuo to an oil (184 g).

To the resulting oil (10.45 g, 50 mmol) in heptane (210 mL) at 0 °C was added 1.6 M butyl lithium (45 mL, 72 mmol). This was stirred for 3 h and then quenched with a solution of iodine (22.1 g, 8.7 mmol) in ether (250 mL). The reaction mixture was then stirred for 30 min at 0 °C, quenched with saturated sodium bisulfate (200 mL) and extracted with ether (3 x 250 mL). The combined organics were washed with saturated sodium bisulfate (200 mL), saturated NaCl (200 mL) and dried over sodium sulfate. Concentration in vacuo gave an oil. The crude oil was dissolved in ethanol (250 mL) and pyridinium p-toluenesulfonate was added. The mixture was heated at 70 °C for 1.5 h, cooled to room temperature, diluted with ethyl acetate (250 mL) and washed with saturated NaCl (250 mL). The aqueous layer was extracted twice with ethyl acetate (250 mL). The organics were combined, dried over sodium sulfate and concentrated in vacuo to an oil of compound (39): MS (CI) m/z (rel intensity 250 ([M + I] +100).

To a solution of 2-bromophenol (1.73 g, To a solution of 100 ml of 1,2-dimethyl-2-butoxide (1.12 g, 10 mmol) in DMF (20 ml) at 0 °C was added potassium tert-butoxide (1.12 g, 10 mmol). This was stirred at 0 °C for 15 minutes followed by addition of the compound from Example 38 (3.73 g, 10 mmol). This was heated at 60 °C for 16 hours, cooled to room temperature, diluted with ethyl acetate (200 ml) and washed twice with water (1 x 200 ml, 1 x 100 ml). The organics were dried over sodium sulfate and concentrated in vacuo to ca. 20 ml. This was diluted 1:1 (v/v) with heptane and passed through a pad of silica (1.5 g). The eluent was concentrated in vacuo to give compound (40) (3 g, 80%) as an oil.

Example 2 3-[4-((3aS,9bS)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 2A (3aS,9bS)-cis-9-methoxy-2-(S)-α-methylbenzyl-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole -4-on

5-Methoxycoumarin and N-methoxymethyl-N- trimethylsilylmethyl-(S)-α-methylbenzylamine were treated in an analogous manner as described in Example 1A. 1H NMR (300 MHz, CDCl₃) δ 1.36 (d, 3H), 2.41 (dd, 1H), 3.04 (d, 1H), 3.05-3.15 (m, 2H), 3.23 (m, 1H), 3.32 (1, 1H), 3.75 (m, 1H), 3.79 (s, 3H), 6.61 (d, 1H), 6.67 (d, 1H), 7.18 (t, 1H), 7.20- 7.35 (m, 5H).

Example 2B (3aS,9bS)-cis-9-methoxy-2-(S)-α-methylbenzyl-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The resulting product from Example 2A was treated in an analogous manner as described in Example 1B. ¹H NMR (300 MHz, CDCl3 ) ? 1.36 (d, 3H), 2.23-2.31 (m, 2H), 2.59 (m, 1H), 3.04 (dd, 1H), 3.20 (q, 1H), 3.23 (q, 1H), 3.38 (q, 1H), 3.77 (s, 3H), 3.81 (q, 1H), 4.01 (q, 1H), 6.41 (d, 1H), 6.52 (d, 1H), 7.04 (t, 1H), 7.20-7.35 (m, 5H).

Example 2C (3aS,9bS)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 2B was treated in an analogous manner as described in Example 1C. 1H NMR (300 MHz, CDCl₃) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H); [α]D MeOH +95.2º.

Example 2D (3aS,9bS)-cis-2-(3-cyanopropyl)-9-methoxy-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 2C was treated in an analogous manner as described in Example 1D. 1H NMR (300 MHz, CDCl₃) δ 1.82 (m, 2H), 2.30 (m, 2H), 2.43 (t, 2H), 2.45-2.65 (m, 3H), 3.04 (dd, 1H), 3.23-3.42 (m, 2H), 3.79 (dd, 1H), 3.82 (s, 3H), 4.06 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).

Example 2E (3aS,9bS)-cis-2-(4-aminobutyl)-9-methoxy-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 2D was treated in an analogous manner as described in Example 15. 1H NMR (300 MHz, CDCl3) δ 1.65-1.80 (m, 4H), 2.19 (m, 1H), 2.25 (dd, 1H), 2.42 (m, 1H), 2.52 (t, 2H), 3.14 (dd, 1H), 3.18-3.30 (m, 2H), 3.79 (dd, 1H), 3.80 (s, 3H), 4.04 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).

Example 2F 3-[4-(3aS,9bS)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]Syrtol-2-yl)butyl ]-pyrido[2'3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 2E (0.800 g, 2.9 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.624 g, 3.00 mmol) are treated as described in Example 1F to give 1.1 g (79%) of the title compound: mp 241-243° (dec); 1H NMR (300 MHz, CDCl3 (free base)) δ 1.56-1.99 (m, 2H), 1.71-1.83 (m, 2H), 2.26 (t, J = 9 Hz, 1H), 2.34 (dd, J = 6, 10 Hz, 1H), 2.50-2.70 (m, 3H), 3.26 (dd, J = 7, 10 Hz, 1H), 3.43 (q, J = 8 Hz, 1H), 3.63 (t, J = 8 Hz, 1H), 3.79 (s, 3H), 3.76-3.86 (m, 1H), 4.01 (dd, J = 4, 11 Hz, 1H), 4.11 (t, J = 7 Hz, 1H), 6.43 (d, J = 8 Hz, 1H). ), 6.49 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 7.49 (dd, J = 4.8 Hz, 1H), 8.23 (dd, J = 1.8 Hz, 1H), 8.78 (dd, J = 1.4 Hz, 1H); MS (DCI (NH3)) nae 479 (M + H)+; Analysis calcd for C25H26N4O4S·HCl·(H2O)0.25: C, 57.80; H, 5.34; N, 10.78; Found: C, 57.85; H, 5.46; N, 10.65.

Example 3 3-[4-(3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 3A 3-(R)-(2-Hydroxy-6-methoxy)phenyl-4-(S)-hydroxymethyl-N-(R)-α-methylbenzylpyrrolidine

Ethyl 2-methoxy-6-methoxymethyl-cinnamate (36 g, 160 mmol) and trifluoroacetic acid (1.23 mL, 16 mmol) were combined in CH₂Ol₂ (800 mL) and cooled to 0 °C. To the stirred solution was added N-methoxymethyl-N-trimethylsilylmethyl-(R)-α-methylbenzylamine (80 g, 320 mmol) in 200 mL of CH2Cl2 over 30 min. The reaction was stirred for an additional 2.5 h at 0 °C. The reaction mixture was washed with 5% NaHCO3, the organic layer was dried and evaporated. The crude product was dissolved in THF (150 mL) and added to a stirred solution of LiAlH4 (12.1 g, 320 mmol). The reaction was quenched (Fieser workup), filtered through Celite and evaporated. The product was dissolved in methanol (850 mL) and 4 N HCl (120 mL) was added. After heating to reflux for 2 h, the solvent was evaporated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic extracts were dried and evaporated. The crude product was purified by chromatography eluting with 2:1 diethyl ether:hexane to give 22.1 g (42%) of the title compound as the faster running diastereomer: 1H NMR (300 MHz, CDCl3) δ. 1.48 (d, 3H), 1.81 (t, 1H), 2.16 (m, 1H), 2.36 (m, 1H), 2.58 (t, 1H), 3.05 (t, 1H), 3.40 (m, 2H), 3.53 (m, 2H), 3.80 (dd, 1H), 3.83 (s, 3H), 6 .38 (d, 1H), 6.60 (d, 1H), 7.05 (t, 1H), 7.22-7.40 (m, 5H), 12.62 (br s, 1H).

Example 3B (3aS,9bR)-trans-9-methoxy-2-(R)-α-methylbenzyl-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 3A (22.1 g, 1.67.0 mmol) was dissolved in 290 mL of a 4:1 mixture of acetonitrile and CCl4. To the solution was added triphenylphosphine (35.4 g, 135 mmol) and the reaction was heated to 80 °C for 20 min. The reaction was concentrated and passed through a silica gel column, eluting with 1:1 hexane:diethyl ether. The product, which contained a mixture of the title compound and the chloro intermediate, was dissolved in THF (300 mL) and 41 mL of 1.0 M potassium t-butoxide in THF was added. After 18 h, the THF was evaporated and the resulting product partitioned between 1 N NaOH and diethyl ether. The organic extracts were dried and evaporated and the resulting product was chromatographed on silica gel, eluting with 1:1 hexane:diethyl ether to give 13.2 g (63%) of the title compound: 1H NMR (300 MHz, CDCl3) ? 1.45 (d, 3H), 2.28 (m, 1H), 2.44 (dd, 1H), 2.70-2.90 (m, 2H), 3.54 (m, 1H), 3.69 (s, 3H), 3.70 (q, 1H), 3.99 (dd, 1H), 4.38 (dd, 1H), 6.37 ( d, 1H), 6.47 (d, 1H), 7.04 (t, 1H), 7.20- 7.40 (m, 5H).

Example 3C (3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 3B (13.0 g, 42 mmol) was treated as described in Example 1C to give 8.08 g (94%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 2.07 (br s, 1H), 2.24 (m, 1H), 2.70 (m, 2H), 2.84 (t, 1H), 3.21 (dd, 1H), 3.77 (s, 3H), 3.83 (dd, 1H), 4.07 (dd, 1H), 4.53 (dd, 1H), 6.40 (d, 1H), 6.51 (d, 1H), 7.06 (t, 1H); [α]D MeOH -94.8º.

Example 3D (3aS,9bR)-trans-2-(3-cyanopropyl)-9-methoxy-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 3C (8.0 g, 39 mmol), 4-bromobutyronitrile (6.3 g, 43 mmol), and diisopropylethylamine (7.6 g, 58 mmol) were treated as described in Example 1D to give 7.1 g (67%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.84 (m, 2H), 2.30 (m, 1H), 2.46 (t, 2H), 2.55 (dd, 1H), 2.70- 2.85 (m, 4H), 2.91 (dd, 1H), 3.52 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H), 4.45 (dd, 1H), 6.39 (d, 1H), 6.49 (d, 1H), 7.05 (t, 1H).

Example 3E (3aS,9bR)-trans-2-(4-aminobutyl)-9-methoxy-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 3D (7.1 g, 26 mmol) was treated as described in Example 1E to give 6.29 g (87%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.40-1.80 (m, 4H), 2.32 (m, 1H), 2.57 (t, 1H), 2.62-2.90 (m, 4H), 2.95 (t, 1H), 3.60 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H), 4.45 (dd, 1H), 6.40 (d, 1H), 6.49 (d, 1H), 7.04 (t, 1H).

Example 3F 3-[4-((3aS,9bR)-ttans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]yrrol-2-yl) butyl] pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.800 g, 2.9 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.624 g, 3.00 mmol) were treated as described in Example 1F to give 0.70 g (50%) of the title compound: mp >255°; 1H NMR (300 MHz, DMSO-d6 (free base)) δ 1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2.04-2.18 (m, 1H), 2.25-2.89 (m, 4H), 3.10-3.48 (m, 3H), 3.68 (s, 3H), 3.95 (t, J = 7 Hz, 2H), 4.02 ( dd, J = 10, 12 Hz, 1H), 4.39 (dd, J = 4, 10 Hz, 1H), 6.39 (dd, J = 1, 8 Hz, 1H), 6.44 (dd, J = 1, 8 Hz, 1H), 7.01 (t, 1 = 8 Hz, 1H), 7.64 (dd, J = 5, 8Hz, 1H), 8.63 (dd, J = 1.8 Hz, 1H), 8.83 (dd, J = 1.5 Hz, 1H); MS (DCI(NH3)) m/e 479 (M + H)+; Analysis calcd for C25H26N4O4S·HCl·(H2O)0.5: C, 57.30; H, 5.39; N, 10.69; Found: C, 57.08; H, 5.43; N, 10.80.

Example 4 3-[-4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrtol-2-yl )butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 4A (3aR,9bS)-trans-2-(4-aminobutyl)-9-methoxy-1,2,3,3a,4,9b -hexahydro-[1]-benzopyrano[3,4-c]pyrrole

Ethyl 2-methoxy-6-methoxymethyl cinnamate and N- Methoxymethyl-N-trimethylsilylmethyl-(S)-α-methylbenzylamine was treated in an analogous manner as described in Examples 3A-E: ¹H NMR (300 MHz, CDCl₃) δ 1.40-1.80 (m, 4H) , 2.32 (m, 1H), 2.57 (t, 1H), 2.62-2.90 (m, 4H), 2.95 (t, 1H), 3.60 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H ), 4.45 (dd, 1H), 6.40 (d, 1H), 6.49 (d, 1H), 7.04 (t, 1H).

Example 4B 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyridö[2',3':4,5]thieno[3,2-d]ovrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 4A (680 mg, 2.5 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (520 mg, 2.5 mmol) were treated as described in Example 1F to give 0.75 g (63%): mp >255°; 1H NMR (300 MHz, DMSO-d6 (free base)) δ 1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2.04-2.18 (m, 1H), 2.25- 2.89 (m, 4H), 3.10-3.48 (m, 3H), 3.68 (s, 3H), 3.95 (t, J = 7 Hz, 2H), 4.02 (dd, J = 10, 12 Hz, 1H), 4.39 (dd, J = 4, 10 Hz, 1H), 6.39 (dd, J = 1, 8 Hz, 1H), 6.44 (dd, J = 1.8 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 7.64 (dd, J = 5, 8Hz, 1H), 8.63 (dd, J = 1.8 Hz, 1H), 8.83 (dd, J = 1.5 Hz, 1H); MS (DCI(NH3) m/e 479 (M + H)+; Analysis calculated for C25H26N4O4S·HCl·(H2C)0.25: C, 57.80; H, 5.34; N, 10.78; Found: C, 57.45; H, 5.35; N, 10.80.

Example 5 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]oyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 5A Methyl 3-amino-5-chlorothieno[3,2-b]pyridine-2-carboxylate and methyl 3-amino-7-chlorothieno[3,2-b]pyridine-2-carboxylate

To a solution of 3-chloro-2-cyanopyridine (40 g, 0.29 mol) in 500 mL of acetic acid was added hydrogen peroxide (30%, 52 g, 0.45 mol) dropwise. After stirring at 90 °C for 18 h, the reaction was cooled to 25 °C and a solution of sodium sulfite (57 g, 0.45 mol) in H 2 O was added dropwise. The reaction was concentrated to remove the excess of acetic acid and the residue was partitioned between 1 M NaOH and CH 2 Cl 2 . The CH 2 Cl 2 Layer was dried (MgSO4), filtered, concentrated to recrystallize from EtOAc to give 23 g (51%) of 3-chloro-2-cyanopyridine N-oxide. The resulting N-oxide (12.2 g, 79 mmol) was dissolved in DMF (160 mL) at 0 °C. Methyl thioglycolate (7.1 mL, 79 mmol) was added in portions followed by sodium methoxide (8.5 g, 160 mmol). The reaction was stirred for 1 h. The reaction was poured onto ice and the resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried (MgSO4), filtered, concentrated and recrystallized from EtOAc. 10.6 g (60%) of methyl 3-amino-thieno[3,2-b]pyridine-4-oxidecarboxylate was obtained. The pyridine N-oxide (10.6 g, 47 mmol) was mixed with phosphorus oxychloride (100 mL). The reaction was heated to 80 °C for 30 minutes. The reaction was concentrated and partitioned between CH2Cl2 and 5% aqueous NaHCO3 solution. The CH2Cl2 Layer was dried (MgSO4), filtered, concentrated, and chromatographed (5:1 Hex:EtOAc) to give methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate (8.3 g, 73%): 1H NMR (300 MHz, CDCl3) d 3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H); MS (DCI/NH3) m/e 243 (M + H)+; followed by methyl 3-amino-7-chloro-thieno[3,2- b]pyridine-2-carboxylate (2.0 g, 18%): ¹H NMR (300 MHz, CDCl₃) d 3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H); MS (DCINH 3 ) mle 243 (M + H) + .

Example 5B 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The Product from Example 4A (0.27 g, 1.0 mmol) and methyl 3-amino-7-chloro-thieno[3,2-b]pyridine-2-carboxylate were treated as described in Example 1F from 0.12 g (24%) to give the title compound: mp 265-267°; 1H NMR (300 MHz, CDCl3 (free base)) δ. 8.63 (d, 1H), 7.51 (d, 1H), 7.08 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.93 (dd, 1H), 4.02-4.18 (m, 3H), 3.99 (m, 1H), 3.38 (t, 1H), 2.88-3.1 2 (m, 5H), 2.45 (m, 1H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/e 513 (M + H) + ; Analysis calculated for C25 H25 N4 O4 SCl.2HCl: C, 51.25; H, 4.64; N, 9.56; Found: C, 51.28; H, 4.96; N, 9.45.

Example 6 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]Dyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione oil hydrochloride

The product from Example 4A (0.27 g, 1.0 mmol) and methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate were treated as described in Example 1F to give 0.10 g (19%) of the title compound: mp >250°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.1 (d, 1H), 7.41 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.35 (d, 1H), 4.57 (dd, 1H), 4.11 (m, 3H), 3.95 (m, 1H), 3.73 (s, 3H), 3.37 (m, 2H), 2. 9-3.1 (m, 4H), 2.48 (m, 1H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/e 513 (M + H) + ; Analysis calculated for C25 H25 ClN4 O4 S·2HCl: C, 51.25; H, 4.64; N, 9.56; Found: C, 51.22; H, 4.77; N, 9.32.

Example 7 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 7A 3-Amino-5-methoxy-thieno[3,2-b]pyridine-2-carboxylate

A solution of 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate (5 g, 21 mmol) and sodium methoxide (4.5 g, 82 mmol) in MeOH (150 mL) was heated to reflux for 18 h. The reaction was concentrated and partitioned between EtOAc and NaHCO3 solution. The EtOAc layer was dried (MgSO4), filtered, concentrated and chromatographed (5:1 Hex:EtOAc) to give 2.5 g (51%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 4.02 (s, 3H), 6.05 (bs, 2H), 6.89 (d, 1H), 7.88 (d, 1H); MS (DCI/NH 3 ) m/e 239 (M + H) + .

Example 7B 3-[4-((3aR,9b5)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

To 0.10 g (0.42 mmol) of the product from Example 7A dissolved in 10 mL of dry THF and cooled to 0 °C was added 2.2 equivalents of triethylamine (0.142 mL) followed by 0.23 mL of a 1.93 M solution of phosgene in toluene. The reaction was stirred for 3 h and then 0.10 g (0.36 mmol) of the product from Example 4A was added. The reaction was stirred at room temperature overnight and then partitioned between aqueous NaHCO3 and CH2Cl2. The organic phase was dried, concentrated and dissolved in THF. Potassium t-butoxide (0.8 mmol in THF) was added. The reaction was stirred at room temperature for 2 h and then partitioned between aqueous NaHCO3 and CH2Cl2. After chromatographic purification and conversion to the hydrochloride salt, 0.09 g (48%) of the title compound was isolated: mp 238-240º; 1H NMR (300 MHz, CDCl₃ (free base)) δ. 8.06 (d, 1H), 7.05 (t, 1H), 6.9 (d, 1H), 6.48 (d, 1H), 6.39 (dd, 1H), 4.45 (dd, 18), 4.12 (t, 1H), 4.03 (s, 3H), 4.02 (m, 1H), 3.76 (s, 3H), 3. 59 (q, 1H), 2.96 (q, 1H), 2.78 (m, 4H), 2.56 (m, 1H), 2.31 (m, 1H), 1.79 (m, 2H), 1.63 (m, 2H); MS (DCI/NH₃) m/e 509(M + H)⁺; Analysis calculated for C₂₆H₂₈N₄O₅S·HCl·0.5H₂O: C, 56.36; H, 5.46; N, 10.11; Found: C, 56.56; H, 5.41; N, 9.97.

Example 8 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 8A

3-Amino-7-methoxy-thieno[3,2-b]pyridine-2-carboxylate Following the procedure described in Example 7A, 3- Amino-7-chloro-thieno[3,2-b]pyridine-2-carboxylate (2.0 g, 8.2 mmol) gave 1.1 g (56%) of the title compound after chromatography with 1:1 Hex:EtOAc.: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 4.05 (s, 3H), 6.18 (bs, 2H), 6.81 (d, 2H), 8.52 (d, 2H); MS (DCI/NH3) m/e 239 (M + H)+.

Example 8B 3-[4-((3aR,9bS)-trans-9-Methoxv-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

To 0.24 g (1 mmol) of the product from Example 8A dissolved in 10 mL of dry THF and cooled to 0 °C was added 2.2 equivalents of triethylamine (0.37 mL) followed by 0.6 mL of a 1.93 M solution of phosgene in toluene. The reaction was stirred for 3 h and then 0.276 g (1.00 mmol) of the product from Example 4A was added. The reaction was stirred at room temperature overnight and then partitioned between aqueous NaHCO3 and CH2Cl2. The organic layers were dried, concentrated and dissolved in THF. Potassium t-butoxide (lmmol in THF) was added. The reaction was stirred at room temperature for 2 h and partitioned between aqueous NaHCO3 and CH2Cl2. After chromatographic purification and conversion to the dihydrochloride salt, 0.26 g (49%) of the title compound was isolated: mp 191-193°; 1H NMR (300 MHz, CDCl3 (free base)) 8.63 (d, 1H), 7.1 (t, 1H), 6.92 (d, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.51 (dd, 1H), 4.15 (m, 6H), 3.78 (s, 3H), 3.6 (m, 1H), 3.0-3.3 (m, 6H), 2.52 (m, 1H), 1.85 (m, 4H); MS (DCI/NH3) m/e 509 (M + H)+; Analysis calcd for C26H28N4O5; S·2HCl·H2O: C, 52.09; H, 5.38; N, 9.34; Found: C, 51.85; H, 5.47; N, 9.00.

Example 9 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano(3,4-c)pyrrol-2-yl) butyll-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 9A 2-chloro-3-cyano-5-phenylpyrazine and 2-chloro-3-cyano-6-phenylpyrazine

A mixture of 5- and 6-phenyl regioisomers of 2-hydroxy-3-carboxamidepyrazine (7.2 g, 33.5 mmol) prepared by the method of R. G. Jones, J. Am. Chem. Soc. 71:78 (1949) was combined with phosphorus oxychloride (56 mL, 586 mmol) and triethylamine (9.3 mL, 67 mmol) and heated to reflux for 2 hours. The mixture was evaporated to give a black oil which was extracted with ether (3 x 100 mL); the combined extracts were washed with 300 mL of 10% Na2CO3, after which the aqueous layer was briefly extracted with ether. The combined organic layers were removed with activated carbon and filtered through celite, and then evaporated to give a white solid as a 60:40 mixture of the 5- and 6-phenyl isomers; mp: (mixture) 121-125 °C. 1H NMR (300 MHz CDCl3) δ 7.52 (m, 5H major and minor), 8.02 (d, 2H (major), 8.11 (d, 2H (minor)), 9.0 (s, 1H (major)), 9.05 (s, 1H (minor)). MS (DCI/NH3) m/e 215 (M)+.

Example 9B Methyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate

The product from Example 9A (1.20 g, 5.58 mmol) was treated sequentially with methyl thioglycolate (0.65 g, 6.14 mmol) and sodium methoxide (0.60 g, 11.2 mmol) in anhydrous DMF (5 mL) and the reaction was stirred at 25° for 1 hour. The reaction mixture was diluted with water, the product collected by filtration and purified by column chromatography on silica gel eluting with CH2Cl2 to give 0.80 g (first elution isomer) (47%) of the title compound as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 3.75 (s, 3H), 6.25 (br s, 2H), 7.53 (m, 3H), 8.09 (d, 2H), 9.09 (s, 1H). MS (DCI/NH 3 ) m/e 286 (M + H) + .

Example 9C 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 4A (0.10 g, 0.42 mmol) and the product from Example 9B (0.14 g, 0.43 mmol) were treated as described in Example 1F to give 0.03 g (13%) of the title compound: m.p. >250º; 1H NMR (300 MHz, CDCl3 (free base)) δ 9.18 (s, 1H), 8.11 (m, 2H), 7.6 (m, 3H), 7.1 (t, 1H), 6.5 (d, 2H), 6.38 (dd, 1H), 4.5 (dd, 1H), 4.18 (m, 3H), 4.1 (m, 1H), 3.8 (s, 3H), 3.18 (m , 6H), 2.5 (m, 1H), 1.7-1.9 (m, 4H); MS (DCI/NH 3 ) m/e 556 (M + H) + ; Analysis calculated for C30 H29 N5 O4 S·HCl·2H2 O: C, 57.36; H, 5.46; N, 11.15; Found: C, 57.40; H, 5.27; N, 10.79.

Example 9D Alternative synthesis of methyl 7-amino-3-phenylthieno[2,3- b]pyrazine-6-carboxylate

In a flask were charged phenylglyoxime, 30 (44 g, 0.3 mol) and aminomalononitrile tosylate salt, 31 (75 g, 0.3 mol) and 518 ml of isopropanol. This was incubated at room temperature for 2 days. The reaction was then cooled to 0 °C for 4 hours and the solid collected by filtration. The product was washed with 400 mL of cold isopropanol and dried in the oven at 50 °C for 14 hours to give 60 g (95% yield) of the pyrazine ( 32 ): 1HNMR (300 MHz, DMSO d 6 ) δ 9.18 (s, 1H), 8.08 (br s, 2H), 7.99-7.92 (m, 2H), 7.52 7.40 (m, 3H); 13CNMR (75.5 MHz, DMSO-d 6 ) δ 149.6, 142.2, 134.2, 131.3, 129.3, 128.8, 125.7, 115.2, 111.1.

A flask was charged with compound 32 (60 g, 0.28 mol) and 230 mL (1.34 mol) of triethyl phosphite. This was heated to 100 °C for 7.5 hours. The solution was then cooled to room temperature and quenched with 480 mL of water. The slurry was stirred for 12 hours and filtered. The filter cake was washed with 200 mL of 10% ethanoic water and dried in a vacuum oven at 40 °C for 24 hours to give 53 g (95% yield) of compound (33); 1HNMR (300 MHz, CDCl₃) δ 8.96 (s, 1H), 8.05-7.95 (m, 2H), 7.55-7.4 (m, 5H); 13 CNMR (75.5 MHz, CDCl3 ) ? 155.9; 145.0, 140.9, 135.2, 128.9, 128.6, 125.2, 116.1, 110.0; mp 181.5°C.

A flask was charged with copper(II) bromide (67.3 g, 0.3 mol) and DMF (300 mL). This was heated to ca. 60 °C. To the heated solution was added 46.5 g (0.45 mol) of t-butyl isonitrile. After stirring for ca. 2-5 minutes, compound 33 (58.85 g, 0.3 mol) was added portionwise. This was stirred at 60 °C for 20 minutes. The contents were then cooled to ca. 15 °C and poured into 2.5 L of 5% hydrochloric acid which had been pre-chilled to 5 °C. This was stirred for 20 minutes and extracted with 600 mL of methylene chloride. The aqueous layer was again extracted with 100 mL of methylene chloride and the organic layers were combined. The organic layers were washed with 4 x 11 water and 300 mL of brine. 100 g of sodium sulfate and 50 g of silica were then added to the organics. This was stirred and filtered. The filter cake was quenched with methylene chloride to remove the product. The combined filtrate and washings were then distilled to a solid at not more than 40ºC. Drying at 30ºC under vacuum gave 56.5 g (72% yield) of the Compound (34): 1 H NMR (300 MH2 , DMSO-d6 ) ? 8.95 (s, 1H), 8.04- 8.01 (m, 2H), 7.58-7.51 (m, 3H); ¹³CNMR (75.5 MHz, DMS-d 6 δ 151.8, 143.8, 140.4, 133.2, 132.2, 131.5, 129.5, 127.1, 114.8.

In a flask was charged sodium carbonate (5.03 g, 0.05 mol), methyl thioglycolate (5.03 g, 0.05 mol) and 400 mL of methanol. To this was added compound 34 (13.01 g, 0.05 mol). This was stirred at room temperature for 1 hour and then heated to 60 °C for 1.5 hours before cooling to 4 °C for 2 hours. The solid was collected by filtration and washed with cold methanol (40 mL) and dried to give 15.6 g of the impure title compound. The solid was mixed with silica gel (29 g) and washed with ca. 1.51 methylene chloride. The organics were concentrated in vacuo to give the title compound (35) (10.5 g): 1HNMR(300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.41-8.35 (m, 2H), 7.6-7.5 (m, 3H), 7.2 (br s, 2H), 3.87 (s, 3H); mp 197-198 °C.

Example 9E Alternative synthesis of methyl 7-amino-3-phenylthieno[2,3- b]pyrazine-6-carboxylate

To a slurry of distilled water (25 mL), malononitrile (72 g, 1.09 mol) and acetic acid (2.18 g, 0.036 mol) was added sodium nitrite (75.3 g, 1.09 mol) dissolved in water (300 mL). The reaction mixture was stirred for 2 hours and then slowly passed over toluenesulfonyl chloride (200 g, 1.05 mol) dissolved in acetonitrile (463 g) cooled to 12 °C. After the addition was complete, the reaction mixture was slowly quenched in water (2.6 L). The resulting slurry was stirred at room temperature and then the solid formed was filtered, washed with water (2 x 1 L) followed by heptane (200 mL). The solids were dried under vacuum to give compound (50) (242 g, 92%): 1HNMR (300 MHz, CDCl3) δ 7.80 (d, J = 7 Hz), 7.35 (d, J = 7 Hz), 2.41 (s 3H).

Pyrrolidine (10 g, 0.14 mol) and sodium sulfate (5 g) were added to a flask and cooled to < 0ºC. Phenylacetaldehyde (2.4 g, 0.02 mol) was slowly added to the flask to maintain the temperature < 2 °C. The mixture was stirred at 0 °C for 1 h. The reaction was filtered and the solids were washed with 10 mL of heptane. The combined filtrates were distilled (< 40 °C) under vacuum to an oil. Heptane (30 mL) was added and then redistilled to an oil. The final oil was mixed with dimethylformamide (6 mL) and triethylamine (6.06 g, 0.06 mol). The mixture was then slowly added to a flask containing compound 50 (4.98 g, 0.02 mol) in DMF (20 mL) at 0 °C ± 3 °C. This reaction mixture was stirred at 0 °C for 30 min and then thiophenol (2.4 g, 0.022 mol) was added. This mixture was stirred for 3 h at room temperature before water (100 mL) was added. This was stirred for 20 min at room temperature and the solid filtered. The filter cake was slurried with 50 mL of methanol and stirred for 20 min and filtered. The solid was washed with 10 mL and dried to give a grey solid of compound (51) (2.98 g, 51%). 1HNMR (300 Mhz, CDCl₃) d8.9 (s, 1H), 8.0-7.9 (m, 2H), 7.7-7.6 (m, 2H), 7.6-7.45 (m, 6H).

To a solution of compound (51) (2.89 g, 10 mmol) in acetic anhydride (25 mL) and chloroacetic acid (10 g, 106 mmol) was added 30% aqueous hydrogen peroxide (10 g, 88 mmol) at 0 °C. The solution was stirred at room temperature for 1 h and heated to 35 °C for 6 h. The mixture was cooled to room temperature, diluted with water (25 mL) and methanol (25 mL), stirred at room temperature for 30 min and filtered. The filter cake was washed with 50% aqueous methanol (40 mL) and dried to give compound (52) (2.9 g, 90%): 1HNMR(DMSO-d₆) δ 9.60 (1H, s), 8.21 (2H, dd, J = 7.6, 1 Hz), 8.07 (2H, dd, J = 7.6, 1 Hz), 7.83 (1H, dt, J = 7.6, 1 Hz), 7.73 (2H, m), 7.60 (3H, m); 13 CNMR (DMSO-d6 ); &delta; 113.96, 126.13, 128.04, 129.01, 129.39, 129.81, 132.20, 132.91, 135.24, 136.97, 144.72, 153.14, 154.21.

A suspension of the sulfone (52) (30 mg, 0.09 mmol), sodium carbonate (0.1 g, 0.9 mmol) and methyl thioglycolate (20 mg, 0.19 mmol) in methanol (3 ml) was stirred at room temperature for 30 minutes and then at 50 °C for 2 hours. After vacuo concentration, the residue was treated with silica gel (1.5 g) and eluted with methylene chloride (50 ml). Concentration in vacuo gave the title compound (15 mg, 58%).

Example 10 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrand[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 10A 2-Chloro-3-cyanopyrazine-4-oxide

2-Chloro-3-cyanopyrazine (5.00 g, 35.94 mmol) was dissolved in 35 mL of concentrated H4SO4 under nitrogen and cooled to 0 °C. To this was added portionwise 11.65 g (43.95 mmol) of K2S2O8. The flask was equipped with a CHCl3 drying tube, the reaction mixture was warmed to room temperature and stirred for 24 h. After partitioning between CHCl3 and ice water, the separated aqueous layer was extracted with CHCl3. The combined organics were washed with water, saturated NaHCO3 and brine and dried over MgSO4. Concentration afforded 2.01 g (36%) of the title compound as an off-white solid. 1 H NMR (300 MHz, CDCl3 ) ? 8.12 (d, 1H), 8.38 (d, 1H). MS (DCI/NH3 ) m/e 173 (M + NH4 )+.

Example 10B Ethyl-7-aminothieno[2,3-b]pyrazine-6-carboxylate-1-oxide

The compound obtained as Example 10A (2.90 g, 18.64 mmol) was dissolved in 100 mL of DMF under nitrogen and treated with ethyl thioglycolate (2.24 g, 18.64 mmol). After cooling the solution to 0 °C, it was treated with solid NaOEt (2.54 g, 37.29 mmol) at room temperature and then at 13 hours. The reaction mixture was partitioned between ethyl acetate and brine and the layers separated. After extracting the aqueous layers with ethyl acetate, the combined organic layers were washed with water, brine, and dried over MgSO4. Concentration gave a yellow solid which was purified by column chromatography on silica gel eluting with 2:1 then 1:1 hexanes:ethyl acetate to give 3.50 g (78%) of the title compound as a yellow solid: mp 126-127 °C; 1H NMR (300 MHz, CDCl3) δ 1.40 (t, 3H), 4.38 (q, 2H), 7.25 (br s, 2H), 8.02 (d, 1H), 8.41 (d, 1H); MS (DCI/NH3) m/e 240 (M + H)+, 257 (M + NH4)+; Analysis calcd for C9H9N3O3S: C, 45.18; H, 3.79; N, 17.56; Found: C, 44.94; H, 3.77; N, 17.47.

Example 10C Ethyl 7-amino-2-chloro-thieno[2,3-b]pyrazine-6-carboxylate

The compound resulting from Example 88B (0.88 g, 3.68 mmol) was dissolved in 50 mL of POCl3 under nitrogen and heated to 95 °C for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. After extracting the aqueous layer with ethyl acetate, the combined organic layers were washed with water, saturated NaHCO3, brine and dried over Na2SO4. Concentration gave a mixture of two components which was separated by column chromatography on silica gel using a gradient eluting with 10:1 to 1:1 hexanes:ethyl acetate to give 0.56 g (59%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.41 (t, 3H), 4.40 (q, 2H), 6.11 (br s, 2H), 8.60 (s, 1H); MS (DCI/NH 3 ) m/e 258 (M + H) + , 275 (M + NH 4 ) + .

Example 10C 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product resulting from Example 4A (0.25 g, 0.95 mmol) and the product from Example 10C (0.25 g, 1.1 mmol) were treated as described in Example 1F to give 0.15 g (29%) of the title compound: mp 266-267º; 1H NMR (300 MHz, CDCl₃ (free base)) δ 8.7 (d, 1H), 7.53 (d, 1H), 7.1 (t, 1H), 6.5 (d, 1H), 6.4 (dd, 1H), 4.51 (dd, 1H), 4.14 (t, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 3.55 (m, 1H), 3.02- 3.32 (m, 5H), 2.58 (m, 2H), 1.85 (m, 4H); MS (DCI/NH 3 ) m/e 514 (M + H) + ; Analysis calculated for C25 H25 CIN4 O4 S·HCl·1.5H2 O: C, 52.09; H, 5.07; N, 9.72; Found: C, 52.21; H, 4.87; N, 9.60.

Example 11 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopytano[3,4-c]pyrrol-2-yl) butyl]-1-(2-Methoxyethyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 11A Ethyl 7-(N-(2-methoxyethyl)amino)thieno[2,3-b]pyrazine-6-carboxylate

Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (1.0 g, 4.48 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12:513 (1975), was treated with potassium bis(trimethylsilyl)amide (0.5 M in toluene, 8.96 mL) in 15 mL of THF at -70 °C, and warmed to room temperature. 2-Bromoethyl methyl ether (0.454 mL, 4.70 mmol) was added and the reaction was stirred under N2 at 60 °C overnight. The mixture was cooled and evaporated, then purified by column chromatography on silica gel eluting with 1:9 ethyl acetate:hexanes to give 0.640 g (51%) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.25 (q, 2H), 4.32 (t, 2H), 7.70 (br t, 1H), 8.76 (s, 1H); 8.77 (s, 1H); MS (DCI/NH3) m/e 282 (M + H)+.

Example 11B Ethyl 7-(N-(2-methoxyethyl)-N-chlorocarbamoylamino)thieno[2,3- b]pyrazine-6-carboxylate

The product from Example 11A (0.620 g, 2.20 mmol) was reacted with phosgene (1.93 M in toluene, 3.41 mL, 6.6 mmol) and triethylamine (0.767 mL, 5.5 mmol) to give the title compound (0.582 g, 81%) as a yellow oil: 1H NMR (300 MHz DMSOd6) δ 1.31 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.23 (q, 2H), 4.3 (q, 2H), 8.78 (2 singlet, 2H); MS (DCI/NH3) 344 (M + H)+.

Example 11C 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzoypyrano[3,4-c]pyrrol-2-yl) butyl]-1-(2-Methoxyethyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 4A (0.25 g, 0.95 mmol) was heated to reflux overnight with 0.1 mL of triethylamine and 0.27 g (0.82 mmol) of the product from Example 11B. After workup and chromatography, 0.3 g (68%) of the title compound was isolated as a free base. The product was converted to its HCl salt and recrystallized from ethanol/ether to give the title compound: mp 200-202° 1H NMR (300 MHz, CDCl3 (free base)) δ 8.78 (d, 1H), 8.7 (d, 1H), 7.1 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 5.12 (d, 2H,), 4.5 (dd, 1H), 4.05-4.2 (m, 4H), 3.8 (m, 5H), 3.5 (m, 1H), 3.1 2 (m, 5H), 2.5 (m, 1H), 1.85 (m, 4H); MS (DCI/NH 3 ) m/e 538 (M + H) + ; Analysis calculated for C27 H31 N5 O5 S·HCl·0.75H2 O: C, 55.19; H, 5.75; N, 11.92; Found: C, 55.19; H, 5.49; N, 11.88.

Example 12 3-[4-((3aR,9bS)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (0.32 g, 1.35 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12:513 (1975) and the product from Example 4A (0.31 g, 1.13 mmol) were treated as described in Example 1F to give 0.28 g of the title compound as a free base. The product was converted to an HCl salt and recrystallized from ethanol/ether to give the title compound: mp >250°; 1H NMR (300 MHz, DMSO-d6 (free base)) δ 8.98 (d, 1H), 8.89 (d, 1H), 7.11 (t, 1H), 6.52 (d, 1H), 6.45 (d, 1H), 4, 5 (dd, 1H), 4.2 (m, 1H), 4.1 (m, 1H), 3.92 (m, 2H), 3.73 (s, 3H), 3.0 (m, 1H), 2.6 (m, 5H), 2.3 (m, 1H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/e 480(M + H) + ; Analysis calculated for C24H25N5O4S·2HCl0.5H2O: C, 51.34; H, 5.03; N, 12.47; Found: C, 51.34; H, 4.95; N, 12.32.

Example 13 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 10C (0.27 g, 1.0 mmol) and the product from Example 3E (0.22 g, 0.8 mmol) were treated as described in Example 1F to give 0.22 g (66%) of the title compound: mp >270º; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.61 (s, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.45 (d, 1H), 4.6 (m, 1H), 4.45 (dd, 1H), 4.18 (m, 3H), 3.71 (s, 3H), 3.52 (m, 1H), 3.3 (m, 1H), 3.1 (m, 2H), 2.9 (m, 2H), 2.5 (m, 1H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/e 514 (M + H) + ; Analysis calculated for C24H24ClN5O4S·HCl0.5H2O: C, 51.52; H, 4.68; N, 12.52; Found: C, 51.89; H, 4.38; N, 12.17.

Example 14 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (0.24 g, 1.0 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12:513 (1975) and the product from Example 3E (0.22 g, 0.8 mmol) were treated as described in Example 1F to give 0.16 g (43%) of the title compound: mp 219-222°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.62 (s, 1H), 8.45 (s, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.4 (d, 1H), 4, 5 (dd, 1H), 4.2 (m, 1H), 4.1 (m, 3H), 3.72 (s, 1H), 7.7 (m, 1H), 3.3 ( m, 2H), 3.2 (m, 1H), 3.05 (m, 2H), 2.52 (m, 1H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/.e 480 (M + H) + ; Analysis calculated for C24H25N5O4S·2HCl·0.5H2O: C, 51.34; H, 4.96; N, 12.25; Found: C, 51.45; H, 4.96; N, 12.25.

Example 15 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (0.24 g, 1.0 mmol) prepared by the method of Schneller and Clough, J. Hat. Chem., 12:513 (1975) and the product from Example 15 (0.2 g, 0.75 mmol) were treated as described in Example 1F to give 0.11 g (32%) of the title compound: mp 220-222°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.7 (d, 1H), 8.6 (d, 1H), 7.02 (t, 1H), 6.4 (t, 2H), 4.1 (m, 2H), 3.7-4.0 (m, 4H), 3.7 (s, 3H), 3.52 (m, 2H), 2.6-2.9 (m, 4H), 1.6-1.82 (m, 4H); MS (DCINH₃) m/e 480 (M + H)⁺; Analysis calcd for C₂₄H₂₅N₅O₄S·2HCl: C, 52.18; H, 4.93; N, 12.68; Found: C, 52.56; H, 4.99; N, 12.64.

Example 16 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 10C (0.27 g, 1.0 mmol) and the product from Example 1E (0.20 g, 0.73 mmol) were treated as described in Example 1F to give 0.29 g (77%) of the title compound: mp 220-222º; 1 H NMR (300 MHz, CDCl3 (free base)) 6 8.68 (s, 1H), 7.0 (t, 1H), 6.48 (d, 1H), 6.45 (d, 1H), 4.28 (m, 1H), 4.12 (m, JE), 4.0 (m, 2H), 3.75 (s, 3H), 3.6 (m, 1H), 3.08 (m, 3H), 2.9 (m, 2H), 1.75 (m, 4H); MS (DCI/NH 3 ) m/e 514 (M + H) + ; Analysis calculated for C24H24ClN5O4S·HCl·75H2O: C, 51.11; H, 4.74; N, 12.42; Found: C, 51.09; H, 4.75; N, 12.43.

Example 17 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3E)-dione dihydrochloride

The product from Example 8A (0.24 g, 1.0 mmol) and the product from Example 3E (0.276 g, 1.0 mmol) were treated as described in Example 1F to give 0.26 g (51%) of the title compound; mp 173-174°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.64 (d, 1H), 7.08 (t, 1H), 6.92 (d, 1H), 6.5 (d, 1H), 6.4 (dd, 1H), 6.5 (dd, 1H), 4.5 (dd, 1H), 4.12 (m, 8H), 3.76 (s, 3H), 3.02 (m, 4H), 2.45 (m, 2H), 1.82 (n, 4H); MS (DCI/NH 3 ) m/e 509 (M + H) + ; Analysis calculated for C26 H28 N4 O5 S·2HCl·0.25H2 O: C, 60.86; H, 5.60; N, 10.92; Found: C, 60.84; H, 5.41; N, 10.62.

Example 18 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole-2-vl) butyl]-6-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 8A (0.30 g, 1.26 mmol) and the product from Example 1E (0.345 g, 1.25 mmol) were treated as described in Example 1F to give 0.37 g (58%) of the title compound: m.p. 204-206°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.64 (d, 1H), 7.05 (d, 1H), 6.92 (d, 1H), 6.51 (d, 1H), 6.44 (d, 1H), 4.0-4.18 (im, 6H), 3.8 (s, 4H), 3.6 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 2.6 (m, 3H), 2.3 (m, 2H), 1.78 (m, 2H), 1.64 (m, 2H); MS (DCI/NH 3 ) m/e 509 (M + H) + ; Analysis calculated for C26H28N4O5S·2HCl·2H2O: C, 50.57; H, 5.55; N, 9.07; Found: C, 50.59; H, 5.74; N, 9.05.

Example 19 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 5A (0.24 g, 1.0 mmol) and the product from Example 3E (0.27 g, 1.0 mmol) were treated as described in Example 1F to give 0.08 g (15%) of the title compound: m.p. 266-267°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.7 (d, 1H), 7.53 (d, 1H), 7.1 (t, 1H), 6.5 (d, 1H), 6.4 (dd, 1H), 4.51 (dd, 1H), 4.14 (t, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 3.55 (m, 1H), 3.02- 3.32 (m, 5H), 2.58 (m, 2H), 1.85 (m, 4H); MS (DCI/NH 3 ) m/e 514(M + H) + ; Analysis calculated for C25 H25 CIN4 O4 S·HCl·1.5H2 O: C, 52.09; H, 5.07; N, 9.72; Found: C, 52.21; H, 4.87; N, 9.60.

Example 20 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 5A (0.24 g, 1.0 mmol) and the product from Example 1E (0.27 g, 1.0 mmol) were treated as described in Example 1F to give 0.125 g (25%) of the title compound; mp 180-182°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.63 (d, 1H), 7.51 (d, 1H), 7.05 (t, 1H), 6.48 (d, 18), 6.42 (d, 1H), 4.1 (t, 2H), 4.0 (dd, 1H), 3.73 (m, 1H), 3.7(s, 3H), 3.48 (q, 2H), 3.38 (m, 1H), 3.25 (m, 1H), 2.7 (m, 3H), 2.5 (m, 1H), 2.4 (m, 1H), 1.78 (m, 1H), 1.65 (m, 1H); MS (DCI/NH 3 ) m/e 513 (M + H) + ; Analysis calculated for C₂₅H₂₅ClN₄O₄S·HCl·0.75: C, 53.34; H, 4.92; N, 9.95; Found: C, 53.42; H, 4.65; N, 9.55.

Example 21 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-benz[b]thiophene-2-carboxylate (0.24 g, 0.97 mmol) and the product from Example 3E (0.18 g, 0.6 mmol) were treated as described in Example 1F to give 0.22 g (77%) of the title compound: mp >250º; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.28 (d, 1H), 7.39 (d, 1H), 7.56 (m, 2H), 7.04 (t, 1H), 6.46 (d, 1H), 6.38 (dd, 1H), 4.4 (dd, 1H), 4.24 (t, 2H), 4.0 (t, 1H), 3.71 (s, 3H), 3.6 5 (m, 1H), 3.0 (t, 1H), 2.81 (m, 4H), 2.58 (m, 1H), 2.3 (m, 1H), 1.88 (m, 2H); MS (DCI/NH 3 ) m/e 478 (M + H) + ; Analysis calculated for C26H27N3O4S·HCl: C, 60.75; H, 5.49; N, 8.17; Found: C, 60.65; H, 5.31; N, 8.03.

Example 22 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-benzo[b]thiophene-2-carboxylate (0.13 g, 0.52 mmol) and the product from Example 1E (0.10 g, 0.36 mmol) were treated as described in Example 1F to give 0.11 g (64%) of the title compound: mp 198-199°; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, 1H), 8.4(d, 1H), 7.55 (m, 2H), 7.04 (t, 1H), 6.5 (d, 1H), 6.43 (d, 1H), 4.22 (t, 2H), 4.0 (dd, 1H), 3.78 (s, 3H), 3.72 (m, 1H), 3.48 (m, 1H), 3.39 (m, 1H), 3.11 (m, 1H), 2.55 (m, 3H), 2.2 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H); MS (DCI/NH 3 ) m/e 478 (M + H) + ; Analysis calculated for C26 H27 N3 O4 S·HCl: C, 60.75; H, 5.49; N, 8.17; Found: C, 60.62; H, 5.27; N, 8.03.

Example 23 3-[5-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyraho[3,4-c]pyrrol-2-yl) pentyl]-[1]benzthieno[3,2-d]yrimidine-2,4(1H,3H)-dione hydrochloride Example 23A (3aS,9bR)-trans-2-(4-cyanobutyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 3C (0.12 g, 0.6 mmol), 5-chlorovaleronitrile (0.08 g, 0.69 mmol), and 1.0 mL of ethyldiisopropylamine were heated to reflux in 5 mL of acetonitrile for 6 hours. The solvent was evaporated and the product partitioned between ethyl acetate and water. The organic layer was dried, evaporated, and purified by silica gel column chromatography to give 0.11 g (64%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.05 (t, 1H), 6.49 (d,1H), 6.39 (d,1H),4.46 (dd,1H), 3.77 (s,3H), 3.56 (q, 1H), 2.92 (q, 1H), 2.68-2.88 (m, 4H), 2.57 (q, 1H), 2.42 (t, 2H), 2 .32 (m,1H), 1.71 (m,4H); MS (DCI/NH3 ) m/e 287(M+H)+

Example 23B (3aS,9bR)-trans-2-(5-aminopentyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

Lithium aluminum hydride (0.11 g, 2.88 mmol) was suspended in ether and a solution of 0.13 g (0.96 mmol) of aluminum chloride in ether was added. To the reaction was then added a solution of the product from Example 23A (0.11 g, 0.38 mmol). The reaction was stirred at 25° for 3 hours and then isolated (Fieser workup) to give 0.10 g (90%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.05 (t,1H), 6.49 (d,1H), 6.39 (d1H), 4.45 (dd,1H), 4.05 (q, 1H), 3.77 (s, 3H), 3.58 (q, 1H), 2.93 (q,1H), 2.61-2.88 (m,6H), 2.56 (m,1H), 2.3 (m, 1H), 1.5 (m, 2H), 1.48 (m, 2H); MS (DCI/NH 3 ) m/e 291 (M + H) + :

Example 23C 3-[5-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) pentyl]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-benzo[b]thiophene-2-carboxylate (0.10 g, 0.40 mmol) and the product from Example 23B (0.11 g, 0.38 mmol) were treated as described in Example 1F to give 0.11 g (60%) of the title compound: mp 196-198°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.22 (d, 1H), 7.89 (d, 1H), 7.53 (m, 2H), 7.03 (d, 1H), 6.48 (d, 1H), 6.38 (dd, 1H), 4.41 (dd, 1H), 4.21 (t, 2H), 4.02 (dd, 1H), 3.71 (s, 3H), 3.56 (m, 1H), 2.92 (m, 1H), 2.63-2.86 (m, 3H), 2.52 (m, 1H), 2.3 (m, 1H), 1.87 (m, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.4 (m, 1H); MS (DCI/NH3) m/e 492 (M + H)+; Analysis calcd for C27H29N3O4S·HCl·H2C: C, 59.39; H, 5.91; N, 7.69; Found: C, 59.83; H, 5.71; N, 7.48.

Example 24 3-[5-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,49b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)pentyll- [1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 24A (3aR,9bR)-cis-2-(4-cyanobutyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 1C (0.10 g, 0.5 mmol), 5-chlorovaleronitrile (0.067 g, 0.57 mmol) and 1.0 mL of ethyldiisopropylamine were heated at reflux in 5 mL of acetonitrile for 6 hours. The solvent was evaporated and the product partitioned between ethyl acetate and water. The organic layer was dried, evaporated and purified. by silica gel column chromatography to give 0.08 g (58%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.08 (t, 1H), 6.51 (d, 1H), 6.45 (d, 1H), 4.04 (dd, 1H), 3.82 (s, 3H), 3.78 (m,1H), 3, 4 (m, 2H), 3.06 (q, 1H), 2.6 (m, 1H), 2.48 (q, 2H), 2.39 (t, 2H), 2.25 (m, 2H), 1.71 (m, 4H); MS (DCI/NH3) m/e 287 (M + H)+

Example 24B (3aR,9bR)-cis-2-(5-aminopentyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

Lithium aluminum hydride (0.10 g, 2.63 mmol) was suspended in ether and a solution of 0.11 g (0.82 mmol) of aluminum chloride in ether was added. To the reaction was then added a solution of the product from Example 24A (0.08 g, 0.28 mmol). The reaction was stirred at 25° for 3 hours and then isolated (Fieser workup) to give 0.07 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.08 (t,1H), 6.51 (d, 1H), 6.45 (d, 1H), 4.03 (dd, 1H), 3.8 (s, 3H), 3.78 (m, 1H), 3.45 (m, 2H), 3.12 (q, 1H), 2.68 (t, 2H), 2.6 (m, 1H), 2.43 (m, 2H), 2.18 (m, 2H), 1.5 (m, 2H), 1.38 (m, 2H); MS (DCI/NH3 ) m/e 291 (M + H)+ .

Example 24C 3-[5-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) pentyl]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-benzo[b]thiophene-2-carboxylate (0.10 g, 0.40 mmol) and the product from Example 24B (0.07 g, 0.24 mmol) were treated as in Example 1F to give 0.08 g (69%) of the title compound: mp 128-130°; 1H NMR (300 MHz, CDCl3 (free base)) δ. 8.12 (d, 1H), 7.72 (d, 1H), 7.4 (m, 2H), 7.08 (t, 1H), 6.52 (d, 1H), 6.47 (d, 1H), 4.4 (m, 2H), 4.3 (m, 1H), 4.04 (dd, 1H), 3.7 (s, 3H), 3.5 ( m, 1H), 3.32 (m, 2H), 3.2 (m, 1H), 2.7 (m, 1H), 2.52 (m, 2H), 2.35 (m, 2H), 1.88 (m, 1H), 1.62 (m, 4H); MS (DCI/NH3) m/e 492 (M + H)+; Analysis calcd for C27H29N3O4S·HCl·H2O: C, 59.39; H, 5.91; N, 7.69; Found: C, 59.47; H, 5.94; N, 7.52.

Example 25 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate, prepared as described in Example 6A (0.24 g, 1.0 mmol) and the product from Example 3E (0.20 g, 0.7 mmol) were treated as described in Example 1F to give 0.18 g (50%) of the title compound: mp >250º; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.1 (d, 1H), 7.21 (d, 1H), 7.02 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.56 (dd, 1H), 4.1 (m, 2H), 3.88 (m, 1H), 3.73 (s, 3H), 3.3 (m, 2H), 2.85 -3.12 (m, 4H), 2.44 (m, 2H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/e 513(M + H) + ; Analysis calculated for C25 H25 CIN4 O4 S·2HCl: C, 51.25; H, 4.64; N, 9.56; Found: C, 51.04; H, 4.58; N, 9.27.

Example 26 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-5-methoxy-thieno[3, 2-b]pyridine-2-carboxylate, prepared as described in Example 7A (0.20 g, 0.84 mmol) and the product from Example 3E (0.23 g, 0.84 mmol) were treated as described in Example 1F to give 0.30 g (70%) of the title compound: mp >250°; 1H NMR (300 MHz, CDCl3 (free base)) δ. 8.06 (d, 1H), 7.05 (t, 1H), 6.9 (d, 1H), 6.48 (d, 1H), 6.39 (dd, 1H), 4.45 (dd, 1H), 4.12 (t, 1H), 4.03 (s, 3H), 4.02 (m, 1H), 3.76 (s, 3H), 3. 59 (q, 1H), 2.96 (q, 1H), 2.78 (m, 4H); MS (DCI/NH 3 ) m/e 509 (M + H) + ; Analysis calculated for C26 H26 N4 O5 S·HCl·0.25H2 O: C, 56.82; H, 5.41; N, 10.19; Found: C, 56.68; H, 5.19; N, 10.09.

Example 27 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 27A 2-Cyano-3,5-dichloropyridine

3,5-Dichloropyridine N-oxide (10.0 g, 61 mmol), trimethylsilyl cyanide (25 mL, 183 mmol) and triethylamine (17 mL, 122 mmol) were combined in acetonitrile (60 mL) and heated to reflux for 6 h. The solvent was evaporated and the residue was partitioned between diethyl ether and 5% aqueous NaHCO3. The organic layer was dried (MgSO4) and the product purified by chromatography on silica gel to give 10.0 g (97%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.92 (d, 1H), 8.58 (d, 1H).

Example 27B 3-Chloro-2-cyano-5-methoxypyridine

The product from Example 27A (0.865 g, 5.0 mmol) was dissolved in THF (10 mL) and 0.27 g of NaOMe was added. After 3 hours and 25 °C, the reaction was quenched in 5% aqueous NaHCO3 solution and extracted with diethyl ether. The organic phase was dried, evaporated, and the residue purified by column chromatography eluting with 70:30 hexanes:ethyl acetate to give 0.27 g (32%, second elution component) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H), 7.29 (d, 1H), 8.28 (d, 1H).

Example 27C Methyl 3-amino-6-methoxy-thieno[3,2-b]oyridine-2-carboxylate

The product from Example 27B (0.168 g, 1.0 mmol) and methyl thioglycolate (0.09 mL, 1.0 mmol) were combined in DMF (2 mL). To this solution was added 0.054 g of NaOMe. After 1 hour, an additional 0.07 g of NaOMe was added. After an additional hour, the reaction was quenched in saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 0.17 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.90 (s, 3H), 3.93 (s, 3H), 6.15 (br s, 2H), 7.44 (d, 1H), 8.36 (d, 1H).

Example 27D 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 27C (0.12 g, 0.50 mmol) and that from Example 3E (0.15 g, 0.47 mmol) were treated as described in Example 1F to give 0.12 g (47%) of the title compound: mp 235-237º; 1 H NMR (300 MHz, CDCl3 ((free base)) δ 8.45 (d, 1H), 7.6 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.38 (d, 1H), 4.45 (dd, 1H), 4.1 (t, 2H), 4.05 (m, 1H). ). m/e 509 (M + H)+; Analysis calculated for C26H28N4O5S·HCl·H2O: C, 55.46; H, 5.55; N, 9.95; Found: C, 55.22; H, 5.30; N, 9.75.

Example 28 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano(3,4-c)pyrrol-2-yl) butyl]-pyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 1E (400 mg, 1.5 mmol), 3-amino-2- carbomethoxythieno[3,2-c]pyridine (0.33 g, 1, 1.6 mmol) (J. Heterocyclic. Chem., 24, 85 (1987)), Et3N (0.50 mL, 3.6 mmol) and phosgene (0.82 mL of 1.93 M solution in toluene, 1.6 mmol) was treated as described in Example 1F to give 0.38 g (55%) of the title compound: mp 207-210°; 1H NMR (300 MHz, CDCl3 (free base)) δ. 1.62-1.75 (m, 2H), 1.80-1.92 (m, 2H), 2.20-2.33 (m, 2H), 2.49-2.65 (m, 3H), 3.15 (bt, J = 8 Hz, 1H), 3.39 (q, J = 8 Hz, 1H), 3.50 (t, J = 8 Hz, 1 H), 3.70-3.79 (m, 1H), 3.75 (s, 3H), 3.98 (dd, J = 4, 9 Hz, 1H), 4.22 (t, J = 7 Hz, 2H), 6.41 (dd, J = 1, 8 Hz, 1H), 6.47 (dd, J = 1, 8 Hz, 1H), 7.03 (t, 3 = 8 Hz, 1H), 7.82 (dd, J = 1.5 Hz, 1H), 8.65 (d, J = 5 Hz, 1H), 9.55 (s, 1H); MS (DCI/NH3) m/e 479 (M + H)+; Analysis calcd for C25H26N4O4S·(HCl)2·(H2O)0.75: C, 53.15; H; 5.26; N, 9.22; Found: C, 53.37; H, 5.11; N, 9.74.

Example 29 3-[4-1(3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 1E (400 mg, 1.5 mmol), 3-amino-2- carbomethoxythieno[2,3-c]pyridine (0.33 g, 1.6 mmol) (J. Heterocyclic. Chem., 24, 85 (1987)), Et3N (0.50 mL, 3.6 mmol) and phosgene (0.82 mL of 1.93 M solution in toluene, 1.6 mmol) were treated as described in Example 1F to give 0.50 g (72%) of the title compound: mp 212-214°; 1H NMR (300 MHz, CDCl3 (free base)) δ 1.61-1.76 (m, 2H), 1.81-1.93 (m, 2H), 2.21-2.31 (m, 2H), 2.50-2.67 (m, 3H), 3.15 (dd, J = 7.9 Hz, 1H), 3.36-3.55 (m, 2H), 3.73-3.82 (m, 1 H), 3.78 (s, 3H), 4.00 (dt J = 5, 11 Hz, 1H), 4.23 (t, 3 = 7 Hz, 2H), 6.42 (d, J = 8 Hz, 1H), 6.48 (d, 3=8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 8.12 (d, J = 6 Hz, 1H), 8.71 (d, J = 6 Hz, 1H), 9.24 (s, 1H); MS (DCI/NH₃)) m/e 479 (M + H)⁺; Analysis calculated for C₂₅H₂₆N₄O₄S·(HCl)₂: C, 54.45; H, 5.12; N, 10.16; Found: C, 54.05; H, 5.24; N, 10.05.

Example 30 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 7A (0.30 g, 1.26 mmol) and the product from Example 1E (0.35 g, 1.26 mmol) were treated as described in Example 1F to give 0.37 g (58%) of the title compound: m.p. 195-197°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.3 (d, 1H), 7.07 (t, 1H), 6.98 (d, 1H), 6.52 (d, 1H), 6.46 (d, 1H), 4.05 (t, 2H), 4.03 (m, 1H), 4.02 (s, 3H), 3.83 (m, 1H), 3.81 (s, 3H), 3.5 (m, 2H), 3.25 (m, 1H), 2.65 (m, 3H), 2.3 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H); MS (DCI/NH 3 ) m/e 509 (M + H) + ; Analysis calculated for C26H28N4O5S·HCl·H2O: C, 55.46; H, 5.55; N, 9.95; Found: C, 55.40; H, 5.62; N, 9.58.

Example 31 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano(3,4-c)pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 31A Ethyl 7-amino-2-methoxy-thieno[2,3-b]pyrazine-6-carboxylate

The compound from Example 10C (0.700 g, 2.72 mmol) was dissolved in 75 mL of MeOH, treated with NaOMe (1.47 g, 27.2 mmol) and the resulting solution heated to reflux for 12 hours. The reaction mixture was partitioned between saturated NH4Cl and CHCl3. After extracting the aqueous phase with CHCl3, the combined organics were washed first with water, then with brine, and then dried over Na2SO4. Concentration afforded 0.500 g (77%) of pure title compound as a yellow solid: mp 181-182 °C; 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 4.05 (s, 3H), 6.02 (br s, 2H), 8.30 (s, 1H); MS DCI/NH3) m/e 240 (M + H)+, 257 (M + NH4)+. Analysis calcd for C9H9N3O3S: C, 45.18; H, 3.79; N, 17.56; Found: C, 45.25; H, 3.48; N, 17.41.

Example 31B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 31A (0.30 g, 1.26 mmol) and the product from Example 1E (0.35 g, 1.26 mmol) were treated as described in Example 1F to give 0.33 g (52%) of the title compound: m.p. 182-184°; 1H NMR (300 MHz, DMSO-d6 (free base)) δ 8.58 (s, 1H), 7.13 (t, 1H), 6.61 (d, 1H), 6.52 (d, 1H), 4.1 (m, 1H), 4.08 (s, 3H), 3.96 (t, 2H), 3.85 (m, 1H), 3.8 (s, 3H), 3.42 (m, 2H), 3.1 (m, 2H), 2.85 (m, 3H), 2.75 (m, 2H), 1.68 (m, 4H); MS (DCI/NH 3 ) m/e 510 (M + H) + ; Analysis calculated for C25H27N5O5S·HCl·2H2O: C, 51.59; H, 5.54; N, 12.03; Found: C, 51.67; H, 5.43; N, 11.84.

Example 32 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 32A Methyl 3-amino-5-chloro-thieno[2,3-b]pyridine-2-carboxylate

3-Cyano-2,6-dichloropyridine (5.19 g, 30 mmol) and 2.7 mL (30 mmol) of methyl thioglycolate were combined in DMF and the solution was cooled to 0 °C. To the reaction was added KOH (3.0 g, 54 mmol) in 12 mL of H2O. After 1.5 h at 0 °C, the reaction was diluted with H2O (50 mL) and the precipitate collected. The product was recrystallized from ethyl acetate/hexane to give 1.49 g (20%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 5.90 (br s, 2H), 7.33 (d, 1H), 7.87 (d, 1H).

Example 32B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-bemzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 32A (0.382 g, 1.57 mmol) were treated as described in Example 1F to give 0.30 g (25%) of the title compound: m.p. 201-205°; 1H NMR (300 MHz, CDCl3) δ 1.6-1.9 (m, 4H), 2.2-2.44 (m, 2H), 2.5-5.8 (m, 4H), 3.1-3.9 (m, 4H), 3.78 (s, 3H), 4.02 (dd, 1H), 4.18 (d, 2H), 6.42 (d, 1H), 6.49 (d, 1H), 7.05 (t, 1H), 7.49 (d, 1H), 8.49 (d, 1H); MS (DCI/NH3) m/e 513 (515 (M + H)+; Analysis calcd for C25H26Cl2N4O4S·H2O: C, 52.91; H, 4.97; N, 9.87; Cl, 12.49; Found: C, 53.17; H, 4.87; N, 9.52; Cl, 12.43.

Example 33 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 33A Methyl 3-amino-5-methoxy-thieno[2,3-b]pyridine-2-carboxylate

Sodium metal (0.46 g, 20 mmol) was added to methanol (20 mL) and reacted until the metallic sodium was consumed. To the solution was added the product from Example 32A (0.485 g, 2.0 mmol) and the reaction was heated to reflux for 2 hours. The reaction was quenched in saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 0.410 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 4.02 (s, 3H), 6.74 (d, 1H), 7.77 (d, 1H).

Example 33B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 33A (0.375 g, 1.57 mmol) were treated as described in Example 1F to give 0.480 g (51%) of the title compound: m.p. 210-14°; 1H NMR (300 MHz, CDCl3) δ 1.64-1.88 (m, 4H), 2.2-2.4 (m, 2H), 2.5-2.8 (m, 4H), 3.1-3.9 (m, 4H), 3.78 (s, 3H), 4.02 (dd, 1H), 4.07 (s, 3H), 4.15 (t, 2H), 6.44 (d, 1H), 6.53 (d, 1H), 6.88 (d, 1H), 7.07 (t, 1H), 8.54 (d, 1H); MS (DCI/NH 3 ) m/e 509 (M + H) + ; Analysis calculated for C25H29ClN4O5S·H2O: C, 55.46; H, 5.55; N, 9.95; Cl, 6.30; Found: C, 55.64; H, 5.35; N, 9.91; Cl, 6.24.

Example 34 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H, 3H)-dione hydrochloride

The product from Example 1E (0.414 g, 1.5 mmol) and methyl 3- amino-thieno[2,3-b]pyridine-2-carboxylate (0.328 g, 1.57 mmol) were treated as described in Example 1F to give 0.26 g (34%) of the title compound: mp 195-200°; 1H NMR (300 MHz, CDCl3) δ 1.68-1.9 (m, 4H), 2.3-2.5 (m, 2H), 2.5-2.85 (m, 4H), 3.2-3.9 (m, 4H), 3.79 (s, 3H), 4.01 (dd, 1H), 4.19 (d, 2H), 6.42 (d, 1H), 6.52 (d, 1H), 7.07 (t, 1H), 7.48 (dd, 1H), 8.57 (m, 1H), 8.77 (dd, 1H); MS (DCI/NH 3 ) m/e 497 (M + H) + ; Analysis calculated for C25H27ClN4O4S·H2O: C, 56.33; H, 5.48; N, 10.51; Cl, 6.65; Found: C, 56.32; H, 5.36; N, 10.42; Cl, 6.54.

Example 35 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 35A Methyl 3-amino-5-methyl-thieno[2,3-b]pyridine-2-carboxylate

2-Chloro-3-cyano-6-methylpyridine (1.5 g, 9.8 mmol) and methyl thioglycolate (0.88 mL, 9.8 mmol) were dissolved in DMF (7 mL). To the solution was added 1.0 g of KOH in 5 mL of H2O over 30 min. The reaction was then quenched by the addition of ice water and the product collected by filtration to give 1.72 g (79%) of the title compound: 1HN (300 MHz, CDCl3) δ 2.88 (s, 3H), 3.91 (s, 3H), 5.90 (br s, 2H), 7.17 (d, ZH), 7.82 (d, 1H).

Example 35B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pirido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 35A (0.350 g, 1.57 mmol) were treated as described in Example 1F to give 0.27 g (34%) of the title compound: m.p. 215-20°; 1H NMR (300 MHz, CDCl3) δ 1.68-1.9 (m, 4H), 2.3-2.5 (m, 2H), 2.5-2.8 (m, 4H), 2.71 (s, 3H), 3.2-3.9 (m, 4H), 3.77 (s, 3H), 4.02 (dd, 1H,1H), 4.17 (t, 2H), 6.44 (d, 1 H), 6.53 (d, 1H), 7.07 (t, 1H), 7.34 (d, 1H), 8.41 (d, 1H); MS (DCI/NH 3 ) m/e 493 (M + H) + ; Analysis calculated for C26H29ClN4O4S·1.5H2O: C, 56.16; H, 5.80; N, 10.08; Cl, 6.38; Found: C, 56.00; H, 5.37; N, 10.01; Cl, 5.99.

Example 36 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 36A Methyl 3-amino-4-methoxy-thieno[2,3-b]pyridine-2-carboxylate

To 2-chloro-3-cyano-4-methoxypyridine (2.02 g) and methyl thioglycolate (1.1 mL) in DMF (24 mL) at 5 °C was added a 1.0 M solution of KOtBu/THF (14.6 mL). The reaction was stirred at 5 °C for 20 min, then quenched in saturated NH4Cl at room temperature for 1 h, the solid collected, washed with water and sucked dry. This was recrystallized from EtOAc to give 0.89 g of the title compound.

Example 36B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.414 g, 1.5 mmol) and the product from Example 36A (0.350 g, 1.57 mmol) were treated as described in Example 1F to give 0.40 g (44%) of the title compound: m.p. 180-200°; 1H NMR (300 MHz, CDCl3) δ 1.61 (2H, br), 1.78 (2H, m), 2.23 (2H, br), 2.60 (3H, br), 3.20 (1H, br), 3.45 (2H, br), 3.75 (1H, m), 3.81 (3H, s), 4.03 (1H, dd), 4.10 (1H, t), 4.14 (3H, s), 6.44 (1H, d), 6.51 (1H, d), 6.82 (1H, d), 7.04 (1H, t), 8.60 (1H, d), 8.90 (1H, br s); MS (DCI/NH3 ) m/e 509; Analysis calculated for C26H29ClN4O5S·HCl(H2O)2·(C4H8O2)0.5: C, 53.80; H, 5.97; N, 8.96; Cl, 5.67; Found: C, 53.54; H, 5.68; N, 8.92; Cl, 5.73.

Example 37 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 6A (0.30 g, 1.24 mmol) were treated as described in Example 1F to give 0.30 g (47%) of the title compound: m.p. 196-198°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.15 (d, 1H), 7.47 (d, 1H), 7.05 (t, 1H), 6.48 (d, 1H), 6.42 (d, 1H), 4.08 (d, 2H), 4.02 (dd, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 3.5 (m, 2H), 2. 78 (m, 4H), 2.5 (m, 2H), 1.76 (m, 4H); MS (DCI/NH 3 ) m/e 513 (M + H) + ; Analysis calculated for C25 H25 CINO4 HCl·2H2 O: C, 51.09; H, 5.28; N, 9.25; Found: C, 51.20; H, 5.33; N, 9.55.

Example 38 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 38A Methyl 3-amino-6-chloro-thieno[3,2-b]pyridine-2-carboxylate

The product from Example 27A (3.46 g, 20 mmol) and methyl thioglycolate (1.8 mL, 20 mmol) were combined in 40 mL of THF. To the solution was added 1.08 g of NaOMe (20 mmol). After 1.5 hours, an additional 1.08 g of NaOMe was added and then after an additional 2 hours, the reaction was quenched in 5% aqueous NaHCO3 and extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated, and the product was purified by silica gel column chromatography to give 1.23 g (25%) of the title vet compound: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 6.20 (br s, 2H), 8.04 (d, 1H), 8.54 (d, 1H).

Example 38B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 38A (0.30 g, 1.24 mmol) were treated as described in Example 1F to give 0.29 g (46%) of the title compound: m.p. 224-226°; 1H NMR (300 MHz, DMSO-d6) δ 8.88 (m, 2H), 7.13 (t, 1H), 6.62 (d, 1H), 6.5 (dd, 1H), 4.05 (dd, 1H), 3.96 (t, 2H), 3.82 (m, 1H), 3.8 (s, 3H), 3.2 (m, 2H), 2.95 (m, 1H), 2.85 (m, 3H), 2.3 (m, 2H), 1.7 (m, 4H); Analysis calculated for C25 H25 CIN4 O4 S·HCl·0.75H2 O: C, 53.22; H, 5.16; N, 9.39; Found: C, 53.24; H, 5.04; N, 93.

Example 39 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 9B (0.356 g, 1.25 mmol) were treated as described in Example 1F to give, after recrystallization from methanol, 0.35 g (63%) of the title compound: mp 291º; 1H NMR (300 MHz, CDCl3 (free base)) δ 9.08 (s, 1H), 8.07 (dd, 2H), 7.58 (m, 3H), 6.88 (t, 1H), 6.30 (d, 1H), 6.20 (d, 1H), 4.18 (m, 2H), 3.88 (dd, 1H), 3.72 (s, 3H), 3.63 (m, 2H), 3.38 (m, 2H), 2.72 (m, 3H), 2.6 (m, 1H), 2.5 (m, 1H), 1.8 (m, 4H); MS (DCI/NH 3 ) m/e 556 (M + H + ); Analysis calculated for C30H29N5SO4·HCl: C, 60.85; H, 5.10; N, 11.82; Cl, 5.98. Found: C, 60.50; H, 5.20; N, 11.69; Cl, 6.07.

Example 40 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 40A 3-Cyano-2-chloro-6-phenylpyrazine

3-Carboxamide-2-hydroxy-6-phenylpyrazine (7.56 g, 35.13 mmol), prepared by the method of Dick and Wood, J. Chem. Soc., 1379 (1955) was dissolved in triethylamine (7.11 g, 70.26 mmol), cooled to 0 °C, and dissolved in 50 mL of POCl₃. The mixture was heated to reflux for 3 h before concentration in vacuo. The resulting black oil was extracted 5 x 100 mL of Et₂O and the combined extracts were treated with 250 mL of cold 10% Na₂CO₃. The layers were separated and the organic phase was washed with water and brine and dried over Na₂SO₄. Concentration gave the title compound (3.20 g, 42%) as a tinted solid. mp 143-145 °C; 1H NMR (300 MHz, CDOl3) δ 7.57 (m, 3H), 8.10 (m, 2H), 9.05 (s, 1H); MS (DCI/NH3) m/e 233 (M + NH4)+.

Example 40B Ethyl 7-amino-3-phenyl-thieno[2,3-b]pyrazine-6-carboxylate

The compound from Example 40A (1.00 g, 4.65 mmol) was treated with ethyl thioglycolate (0.56 g, 4.65 mmol) and Na2CO3 (0.49 g, 4.65 mmol) in 20 mL of EtOH. Recrystallization of the crude product from EtOH/H2O gave the title compound (1.19 g, 86%) as a yellow-green solid. mp 173-175 °C. 1H NMR (300 MHz, CDCl3) δ 1.42 (t, 3H), 4.41 (q, 2H), 6.18 (br s, 2H), 7.55 (m, 3H), 8.12 (m, 2H), 9.03 (s, 1H), MS (DCI/NH3 ) m/e 300 (M + H)+.

Example 40C 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.357 g, 1.25 mmol) and the product from Example 40B (0.356 g, 1.25 mmol) were treated as described in Example 1E to give 0.30 g (59%) of the title compound: 1H NMR (300 MHz, CDCl3 (free base)) δ 9.13 (s, 1H), 8.18 (dd, 2H), 7.79 (m, 3H), 7.04 (t, 1H), 6 : 45 (t, 2H), 4.12 (t, 2H), 4.01 (dd, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.55 (m, 2H), 3.45 (m, 1H), 2.78 (m, 3H), 2.62 (m, 2H), 1.78 (m, 4H); MS (DCI/NH 3 ) m/e 556 (M + H) + ; Analysis calculated for C30H29N5SO4·HCl·1.5H2O: C, 58.20; H, 5.37; N, 11.31; Found: C, 58.51; H, 5.31; N, 11.33.

Example 41 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b--hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl )butyl]-pyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 3E (210 mg, 0.75 mmol), 3-amino-2-carbomethoxythieno[3,2-c]pyridine (0.17 g, 0.83 mmol) (J. Heterocyclic Chem., 24, 85 (1987)), Et3N (0.40 mL, 2.9 mmol) and phosgene (0.43 mL of 1.93 M solution in toluene, 0.83 mmol) were treated as described in Example 1F to give 0.20 g (56%) of the title compound: mp >250°; 1H NMR (300 MHz, CDCl3; (free base)) δ. 1.72-1.93 (m, 4H), 2.29-2.43 (m, 1H), 2.74 (t, J = 10 Hz, 1H), 2.83-2.98 (m, 4H), 3.16 (dd, J = 8, 10 Hz, 1H), 3.73 (s, 3H), 3.75-3.83 (m, 1H ). J = 8Hz, 1H), 7.80 (dd, J = 1.6 Hz, 1H), 8.61 (d, J = 6 Hz, 1H), 9.54 (d, J = 1 Hz, 1H); MS (DCI/NH₃)) m/e 479 (M + H)⁺; Analysis calcd for C₂₅H₂₆N₄O₄S·(HCl)2·H₂O·(CH₃OH)0.5: C, 52.31; H, 5.51; N, 9.57; Found: C, 51.95; H, 5.22; N, 9.27.

Example 42 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzoypyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 3E (200 mg, 0.72 mmol), 3-amino-2- carbomethoxythieno[2,3-c]pyridine (0.16 g, 0.79 mmol) (J. Heterocyclic Chem, 24, 85 (1987)), Et3N (0.40 mL, 2.9 mmol), and phosgene (0.41 mL of 1.93 M solution in toluene, 0.79 mmol) were treated as described in Example 1F to give 0.20 g (58%) of the title compound: mp 221-223°; 1H NMR (300 MHz, CDCl2 (free base)) δ 1.76-1.96 (m, 4H), 2,37-2.50 (m, 1H), 2.72-2.82 (m, 1H), 2.89-3.11 (m, 4H), 3.18-3.28 (m, 1H), 3.73 (s, 3H), 3.80-3.89 (m, 1H), 4.04 (dd, J = 1, 9 Hz, 1H), 4.22 (t, J = 7 Hz, 2H), 4.45 (dd, J = 4, 10 Hz, 1H), 6.38 (d, 3 = 8 Hz, 1H), 6.54 (d, J = 8 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 8.10 (d, J = 6 Hz, 1H), 8.64 (d, J = 6 Hz, 1H), 9.19 (s, 1H); MS (DCI/NH₃)) m/e 479 (M + H)⁺; Analysis calcd for C₂₅H₂₆N₄O₄S·(HCl)₂·(H₂O)0.75: C, 53.15; H, 5.26; N, 9.92; Found: C, 53.18; H, 5.18; N, 9.70.

Example 43 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.276 g, 1.00 mmol) and the product from Example 31A (0.25 g, 1.05 mmol) were treated as described in Example 1F to give 0.10 g (50%) of the title compound: 1H NMR (300 MHz, CDCl3 (free base)) ? 8.02 (d, 1H), 7.04 (t, 1H), 6.92 (d, 1H), 6.48 (d, 1H), 6.39 (d, 1H), 5.39 (m, 1H), 4.45 (dd, 1H), 4.11 (t, 2H), 4.04 (m, 1H), 3.76 (s, 3H), 3 .59 (q, 1H), 2.96 (q, 1H), 2.76 (m, 4H), 2.58 (m, 1H), 2.3 (m, 1H), 1.77 (m, 4H), 1.42 (d, 6H); MS (DCI/NH 3 ) m/e 537 (M + H) + ; Analysis calculated for C28H32N4O5S·HCl·1.5H2O: C, 56.04; H, 6.05; N, 9.34; Found: C, 56.04; H, 5.70; N; 9.14.

Example 44 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.276 g, 1.0 mmol) and methyl 3-amino-thieno[2,3-b]pyridine-2-carboxylate (0.229 g, 1.1 mmol) as described in Example 35A were treated as described in Example 1F to give 0.185 g (36%) of the title compound: mp 217-8°; 1H NMR (300 MHz, DMSO-d6) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 2H), 2.8-3.5 (m, 5H), 3.78 (s, 3H), 3.97 (m, 2H), 4.10 (q, 1H), 4.47 (m, 1H), 6.46 (d, 1H), 4.56 (d, 1H), 7.13 (t, 1H), 7.65 (dd, 1H), 8.75 (dt, 1H), 8.84 (dd, 1H), 10.55 (br s, 1H), 12.74 (d, 1H); MS (DCI/NH 3 ) m/e 479 (M + H) + ; Analysis calculated for C25H27ClN4O4S·1.5H2O: C, 55.39; H, 5.57; N, 10.33; Found: C, 55.43; H, 5.17; N, 10.32.

Example 45 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.276 g, 1.0 mmol) and the product from Example 35A (0.244 g, 1.1 mmol) were treated as described in Example 1F to give 0.090 g (17%) of the title compound: mp 243-5°; 1H NMR (300 MHz, DMSO-d6) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 3H), 2.66 (s, 3H), 2.8-3.8 (m, 6H), 3.77 (s, 3H), 3.96 (m, 2H), 4.12 (m, 1H), 4.45 (m, 1H), 6.46 (d, 1H), 6.56 (d, 1H), 7.12 (t, 1H), 7.51 (d, 1H), 8.60 (d, 1H); MS (DCI/NH 3 ) m/e 493 (M + H) + ; Analysis calculated for C26 H29 CIN4 O4 S·H2 O: C, 57.08; H, 5.71; N, 10.24; Found: C, 56.93; H, 5.22; N, 9.94.

Example 46 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.248 g, 0.90 mmol) and the product from Example 33A (0.238 g, 1.0 mmol) were treated as described in Example 1F to give 0.301 g (61%) of the title compound: m.p. 260-3°; 1H NMR (300 MHz, DMSO-d6) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 3H), 2.8-3.6 (m, 6H), 3.74 (s, 3H), 3.95 (m, 2H), 3.97 (s, 3H), 4.07 (t, 1H), 4.28 (m, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.07 (d, 1H), 7.11 (t, 1H), 8.59 (d, 1H); MS (DCI/NH 3 ) m/e 509 (M + H) + ; Analysis calculated for C26H29ClN4O5S·3/4H2O: C, 55.91; H, 5.50; N, 10.03; Cl, 6.35; Found: C, 55.75; H, 5.32; N, 10.00; Cl, 6.44.

Example 47 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.248 g, 0.90 mmol) and the product from Example 32A (0.242 g, 1.0 mmol) were treated as described in Example 1F to give 0.285 g (58%) of the title compound: mp 245-50°; 1H NMR (300 MHz, DMSO-d6) δ 1.6-1.8 (m, 4H), 2.1-2.7 (m, 2H), 2.8-3.6 (m, 5H), 3.77 (s, 3H), 3.8-4.2 (m, 2H), 3.95 (m, 2H), 4.10 (t, 1H), 4.47 (m, 1H), 6.46 (d, 1H), 6. 54 (d, 1H), 7.11 (t, 1H), 7.78 (d, 1H), 8.75 (d, 1H); MS (DCI/NH3 ) m/e 513 (515fM + H)+); Analysis calculated for C₂₅H₂₆Cl₂N₄O₄S·0.5H₂O·0.1HCl: C, 53.42; H, 4.86; N, 9.97; Cl, 13.24; Found: C, 53.25; H, 7.73; N, 9.68; Cl, 13.31.

Example 48 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-chloropyrido[3',4':4,5]thieno[3,2-d]yrimidine-2,4(1H,3H)-dione hydrochloride Example 48A Methyl 3-amino-4-chloro-thieno[3,2-c]pyridine-2-carboxylate

To 3-cyano-2,4-dichloropyridine (653 mg) and methyl thioglycolate (340 µl) in DMF (12 mL) at 5ºC was added a solution of 1.0 M KOtBu/THF (4.5 mL). The reaction was stirred for 20 min at 5º then 1 h at room temperature, then quenched in saturated NH₄Cl, the solid precipitate was collected, washed with water and sucked dry to give 800 mg (88%) of the title compound.

Example 48B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-chloropyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 1E (0.276 g, 1.0 mmol) and the product from Example 48A (0.242 g, 1.0 mmol) were treated as described in Example 1F to give 0.280 g (55%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.75 (4H, br m), 2.40 (2H, br), 2.65 (3H, br), 3.30 (1H, br), 3.50 (2H, br), 3.80 (3H, s), 3.86 (1H, br), 4.02 (1H, dd), 4.10 (1H, t), 6.45 (1H, d), 6. 52 (1H, d), 7.08 (1H, t), 7.79 (1H, d), 8.40 (1H, d); MS (CI(NH 3 )) m/e 513 (M + H) + ; Analysis calculated for C25 H25 ClN4 O4 S·HCl: C, 52.49; H, 4.89; N, 9.79; Found: C, 52.28; H, 4.55; N, 9.44.

Example 49 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-methoxypyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione fumarate Example 49A Methyl 3-amino-4-methoxy-thieno[3,2-C]pyridine-2-carboxylate

The product from Example 48A (1.2 g, 4.9 mmol) and sodium methoxide (1.0 g, 19 mmol) were heated to reflux in 30 mL MeOH for 6 hours. The reaction was partitioned between water and CH2Cl2. The organic layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered and concentrated. Silica gel chromatography (CH2Cl2) gave 1.1 g (78%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.05 (s, 3H), 6.96 (bs, 2H), 7.47 (d, J = 6 Hz, 1H), 8.07 (d, J = 6 Hz, 1H); MS (DCI/NH3 )) m/e 239 (M+H)+.

Example 49B 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-9-methoxypyrido[3',4':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione fumarate

The product from Example 1E (0.140 g, 0.50 mmol), the product from Example 49A (0.145 g, 0.061 mmol), Et3N (0.18 mL, 1.3 mmol), and phosgene (1.1 mL of 1.93 M solution in toluene, 2.1 mmol) were treated as described in Example 1F substituting fumaric acid in place of the salt forming step to give 0.22 g (87%) of the title compound. mp 232-233°; 1H NMR (300 MHz, CDCl3 (free base)) δ 1.60-1.84 (m, 4H), 2.24-2A0 (m, 1H), 2.55- 2.65 (m, 1H), 2.72-2.90 (m, 4H), 2.95-3.03 (m, 1H), 3.60-3.69 (m, 1H), 3.76 (s, 3H), 4.05 (dd, J = 10, 11 Hz, 1H), 4.11 (t, J = 7 Hz, 2H), 4.20 (s, 3H), 4.46 (dd, J = 4, 9 Hz, 1H), 6.39 (d, J = 8 Hz, 1H), 6.48 (d, J = 8 Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 7.39 (d, J = 6 Hz, 1H), 8.16 (d, J = 6 Hz, 1H); MS (CI(NH3)) m/e 509 (M + H)+; Analysis calculated for C26H28N4O5S·C4H4O4·(H2O)0.25: C, 57.27; H, 5.21; N, 8.90; Found: C; 56.96; H, 4.95; N, 8.83.

Example 50 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.276 g, 1.0 mmol) and the product from Example 9B (0.308 g, 1.08 mmol) were treated as described in Example 1F to give 0.41 g (73%) of the title compound: m.p. >250º; 1H NMR (300 MHz, CDCl3 (free base)) δ 9.03 (s, 1H), 8.02 (m, 2H), 7.58 (m, 3H), 7.0 (d, 1H), 6.4 (d, 1H), 6.31 (d, 1H), 3.98 (m, 2H), 4.05 (dd, 1H), 3.85 (t, 2H), 3.62 (m, 1H), 3.0 6 (m, 3H), 2.85 (m, 2H), 2.22 (m, 1H), 1.82 (m, 4H); MS (DCI/NH 3 ) m/e 556 (M + H) + ; Analysis calculated for C30H29N5O4S·HCl·2H2O: C, 57.36; H, 5.46; N, 11.15; Found: C, 57.31; H, 5.23; N, 10.99.

Example 51 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-isopropoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 51A Isopropyl 3-amino-5-isopropoxy-thieno[3,2-b]pyridine-2-carboxylate

Sodium metal (0.47 g, 20 mmol) was added to 2-propanol (150 mL) and the reaction was heated to reflux until all the sodium was consumed. To the resulting solution was added methyl 3-amino-7-chloro-thieno[3,2-b]pyridine-2-carboxylate (prepared as described in Example 5A) (0.50 g, 2.06 mmol) and the solution was heated to reflux for 48 h. The solvent was evaporated and the product was partitioned between aqueous NH4Cl and CH2Cl2. The organic layer was dried, concentrated and the product was purified by silica gel chromatography to give 0.11 g (19%) of the title compound: 1H NMR (300 MHz, CDCl3) 7.85 (d, 1H), 6.91 (d,1H), 5.98 (bs,1H), 5.42 (m, 1H), 5.25 (m, 1H), 1.42 (d, 6H), 1.38 (d, 6H); MS (DCI/NH 3 ) m'e 295 (M + H) + :

Example 51B 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-isopropoxypyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.102 g, 0.37 mmol) and the product from Example 51A (0.11 g, 0.37 mmol) were treated as described in Example 1F to give 0.10 g (50%) of the title compound: 1H NMR (300 MHz, CDCl3 (free base)) δ 8.02 (d, 1H), 7.04 (t, 1H), 6.92 (d, 1H), 6.48 (d, 1H), 6.39 (d, 1H), 5.39 (m, 1H), 4.45 (dd, 1H), 4.11 (t, 2H), 4.04 (m, 1H), 3.76 (s, 3H), 3 .59 (q, 1H), 2.96 (q, 1H), 2.76 (m, 4H), 2.58 (m, 1H), 2.3 (m, 1H), 1.77 (m, 4H), 1.42 (d, 6H); MS (DCI/NH 3 ) m/e 537 (M + H) + ; Analysis calculated for C28H32N4O5S·HCl·1.5H2O: C, 56.04; H, 6.05; N, 9.34; Found: C, 56.04; H, 5.70; N, 9.14.

Example 52 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 52A Methyl 3-amino-5-phenyl-thieno[3,2-b]pyrimidine-2-carboxylate

Methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate, prepared as described in Example 6A (0.243 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.0 mmol), and triethylamine (0.20 mL) were added under N2 to 3 mL of DMF containing [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride (1:1 complex with CH2Cl2). The mixture was stirred at 90 °C for 4 h. The reaction was then cooled and diluted with Et2O. The organic layer was washed with H2O and brine. washed, dried (MgSO4), concentrated and chromatographed (2:1 CH2Cl2:hexane) to give the title compound (140 mg, 50%): 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 3H), 6.30 (bs, 2H), 7.41-7.55 (m, 3H), 7.84 (d, J = 8 Hz, 1H), 8.07-8.13 (m, 3H); MS (DCI/NH3) m/e 285 (M + H)+.

Example 52B 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 3E (0.21 g, 0.75 mmol), the product from Example 52A (235 mg, 0.83 mmol), Et3N (0.26 mL, 1.9 mmol), and phosgene (0.5 mL of 1.93 M solution in toluene, 0.95 mmol) were treated as described in Example 1F to give 0.300 g (72%) of the title compound: mp >250°; 1H NMR (300 MHz, CDCl3 (free base)) δ 1.59-1.71 (m, 2H), 1.74-1.87 (m, 2H), 2.19-2.34 (m, 1H), 2.59 (dd, J = 9, 11 Hz, 1H), 2.72-2.84 (m, 4H), 3.00 (dd, J = 7, 9 Hz, 1H), 3.55-3. 67 (m, 1H), 3.73 (s, 3H), 4.00 (dd, J = 10, 12 Hz, 1H), 4.18 (t, J = 7 Hz, 2H), 4.38 (dd, J = 4, 10 Hz, 1H), 6.38 (dd, J = 1, 8 Hz, 1H), 6.46 (dd, J = 1.8Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.44-7.56 (m, 3H), 7.92 (d, J = 8 Hz, 1H), 8.04-8.11 (m, 2H), 8.26 (d, J = 8 Hz, 1H); MS (DCI/NH3)) m/e 555 (M + H)+; Analysis calculated for C3;₁H3;�0N4O4S·(HCl)2·(H2O)0.5: C, 58.49; H, 5.23; N, 8.80; Found: C, 58.18; H, 5.23; N, 8.47.

Example 53 3-[4-((3aR,9bR-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-6-chloropyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione Example 53A Methyl 3-amino-7-chloro-thieno[2,3-c]pyridine-2-catboxylate

3-Chloro-4-cyanopyridine, prepared as described in J. Heterocyclic Chem., 15, 683 (1978), (2.9 g, 21 mmol) was dissolved in acetic acid (15 mL) and 30% H₂O₂ (15 mL) was added over 5 min. The reaction was stirred at 80° for 18 h. After cooling to room temperature, the white solid product (2.5 g) was collected by filtration and dried. The N-oxide was then dissolved in DMF (50 mL) and methyl thioglycolate (1.45 mL, 16 mmol) was added. Sodium methoxide (0.86 g, 16 mmol) was then added. The reaction was stirred for 1 h, poured into ice/water and the product collected by filtration and dried. The resulting solid was suspended in POCl₃ (40 mL) and heated to reflux for 1 h. The reaction was quenched on ice, extracted with ether and the organic extracts washed several times with aqueous 5% NaHCO:. Silica gel column chromatography (85:15 hexane:ethyl acetate) gave 0.42 g of the minor isomer (methyl 3-amino-5-chloro-thieno[2,3-c]pyridine-2-carboxylate) and 1.05 g of the title compound.

Example 53B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[4',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

The product from Example 1E (0.42 g, 1.5 mmol), the product from Example 53A (0.364 g, 1.5 mmol), Et3N (0.5 mL, 3.0 mmol), and phosgene (1.6 mL, 1.93 M solution in toluene, 3.0 mmol) were treated as described in Example 1F to give 0.26 g (33%) of the title compound: mp 191°; 1H NMR (300 MHz, CDCl3) δ 1.7-1.8 (m, 2H), 1.8-1.9 (m, 2H), 2.32-2.55 (m, 2H), 2.60-2.80 (m, 3H), 3.27 (m, 1H), 3.40-3.90 (m, 4H), 3.78 (s, 3H), 4.01 (dd, 1H), 4.19 (t, 2H), 6.43 (d, 1H), 6.48 (d, 1H), 7.06 (t, 1H), 8.04 (d, 1H), 8.46 (d, 1H); MS (DCI/NH 3 ) m/e 513, 515 (M + H) + ; Analysis calculated for C25H25ClN4O4S·H2O: C, 56.55; H, 5.12; N, 10.55; Found: C, 56.32; H, 5.03; N, 10.44.

Example 54 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-6-chloropyrido[4',3':4,5]thieno[3,2-d]pyramidine-2,4(1H,3H)-dione

The product from Example 3E (0.42 g, 1.5 mmol), the product from Example 53A (0.364 g, 1.5 mmol), Et3N (0.5 mL, 3.0 mmol), and phosgene (1.6 mL of 1.93 M solution in toluene, 3.0 mmol) were treated as described in Example 1F to give 0.31 g (40%) of the title compound: mp 230°; 1H NMR (300 MHz, CDCl3) δ 1.50-1.75 (m, 4H), 2.18 (m, 1H), 2.66 (t, 1H), 2.82 (m, 4H), 3.07 (t, 1H), 3.1-3.9 (m, 5H), 3.71 (s, 3H), 3.95 (m, 2H), 4.05 (dd, 1H), 4.42 (dd, 1H), 6.40 (d, 1H), 6.47 (d, 1H), 7.04 (t, 1H), 8.21 (d, 1H), 8.50 (d, 1H); MS (DCI/NH 3 ) m/e 513, 515 (M + H) + ; Analysis calculated for C25H25ClN4O4S·0.5H2O: C, 57.52; H, 5.02; N, 10.73; Found: C, 57.33; H, 4.72; N, 10.73.

Example 55 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 55A Methyl 2-amino-5-methoxy-thieno[2,3-b]pyridine-2-carboxylate

To 2-chloro-3-cyano-5-methoxypyridine (0.53 g) and methyl thioglycolate (280 µL) in DMF (10 mL) at 5 °C was added a 1.0 M solution of KOtBu/THF (3.8 mL). The reaction was stirred at 5 °C for 20 min, then quenched in saturated NH₄Cl for 2 h at room temperature and the solid precipitate was collected, washed with water and dried to give 0.53 g (71%) of the title compound.

Example 55B 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 3E (0.223 g, 0.80 mmol) and the product from Example 55A (0.192 g, 0.80 mmol) were treated as described in Example 1F to give 0.315 g (77%) of the title compound: mp 207-213°; 1H NMR (300 MHz, DMSO-d6) δ 1.5 (2H, m), 1.65 (2H, m), 2.12 (1H, m), 2.57 (1H), 2.7 (4H, m), 2.9.(1H, t), 3.48 (1H, m), 3.7 (3H, s), 3.92 (3H, s), 3.94 (2H), 4.02 (1H, dd), 4.4 (1H, dd), 6.4 (1H, d), 6.45 (1H, d), 7.02 (1H, t), 8.32 (1H, d), 8.56 (1H, d); MS (CI(NH3 )) rm/e 509; Analysis calculated for C26H29ClN4O5: C, 54.59; H, 5.64; N, 9.79; Found: C, 54.61; H, 5.60; N, 9.72.

Example 56 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-berizopyrario[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 56A Methyl 3-amino-5-(3-pyridyl)thienyl[3,2-b]pyridine-2-carboxylate

A solution of methyl 3-amino-5-chloro-thieno[3,2- b]pyridine-2-carboxylate prepared as described in Example 5A (0.252 g), diethyl 3-pyridyl-borane (0.155 g), Pd(dppf)Cl₂ (0.082 g) and K₂CO₃ (420 mg) in degassed DMF (5 mL) was heated to 95 °C for 1.5 h, cooled, quenched in saturated NH₄Cl, the solid precipitate collected and chromatographed with 9:1 hexane/EtOAc to give 0.24 g (81%) of the title compound: 1H NMR (300MH, CDCl₃) δ 3.95 (3H, 's), 6.30 (2H, br s), 7.45 (1H, dd), 7.86 (1H, d), 8.19 (1H, d), 8.42 (1H, dt), 8.70 (1H, dd), 9.32 (1H, br d).

Example 56B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 1E (0.127 g, 0.46 mmol) and the product from Example 56A (0.14 g, 0.49 mmol) were treated as described in Example 1F to give 0.09 g (33%) of the title compound: m.p. 210-211°; 1H NMR (300 MHz, CDCl3) δ 9.3 (d, 1H), 8.73 (dd, 1H), 8.41 (dt, 1H), 8.37 (d, 1H), 7.99 (d, 1H), 7.48 (dd, 1H), 7.12 (t, 1H), 6.53 (d, 1H), 6.48 (d, 1H), 4.12 (t, 2H), 4.0 (dd, 1H), 3.81 (s, 3H), 3.78 (m, 1H), 3.42 (m, 2H), 3.1 (m, 1H), 2.6 (m, 3H), 2.2 (m, 2H), 1.85 (m, 2H), 1.68 (m, 2H); MS (DCI/NH3) m/e 556 (M + H)+; Analysis calcd for C30H29N5SO4·2HCl: C, 57.33; H, 4.97; N, 11.14; Found: C, 57.04; H, 5.09; N, 10.89.

Example 57 3-[4-((3aR, 9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 57A Methyl 7-amino-2-(3-thienyl)thieno[2,3-b]pyrazine-6-carboxylate

A solution of methyl 7-amino-2-chloro-thieno[2,3- b]pyrazine-6-carboxylate prepared as described in Example 100 (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)Cl₂ (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95 °C for 4 h, cooled, quenched in water and extracted with 1:1 Et₂O/EtOAc (3x). The organics were washed 3x with water and brine, dried (Na₂SO₄), filtered and the solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl₃) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).

Example 57B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2'3':4,5]thieno[3,2-d]pyrimidine-2,4(1H 3H)-dione dihydrochloride

The product from Example 1E (0.127 g, 0.46 mmol) and the product from Example 57A (0.13 g, 0.45 mmol) were treated as described in Example 1F to give 0.09 g (36%) of the title compound: 1H NMR (300 MHz, CDCl3 (free base)) δ 9.06 (s, 1H), 8.1 (dd, 1H), 7.78 (dd, 1H), 7.53 (dd, 1H), 7.05 (t, 1H), 6.45 (dd, 2H), 4.13 (t, 2H), 4.01 (dd, 1H), 3.83 (m, 1H), 3.8 (s, 3H), 3.52 (m, 2H), 3.3 (m, 1H), 2.72 (m, 3H), 2.45 (m, 2H), 1.85 (m, 2H), 1.68 (m, 2H); MS (DCI/NH 3 ) m/e 562 (M + H) + ; Analysis calculated for C28H27N5O4S2·HCl·2H2O: C, 53.00; H, 5.09; N, 11.04; Found: C, 52.78; H, 4.84; N, 10.72.

Example 58 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-(3-pyridyl)-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trihydrochloride

The product from Example 3E (0.127 g, 0.46 mmol) and the product from Example 56A (0.14 g, 0.49 mmol) were treated as described in Example 1F to give 0.095 g (35%) of the title compound: m.p. 238-241°; 1H NMR (300 MHz, CDCl3 (free base)) δ 9.34 (d, 1H), 8.76 (d, 1H), 8.47 (d, 1H), 8.38 (d, 1H), 7.99 (dd, 1H), 7.52 (dd, 1H), 7.11 (t, 1H), 6.5 (d, 1H), 6.41 (d, 1H), 4.66 (dd, 1H), 4 .51 (m, 2H), 4.2 (m, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 2.83 (m, 1H), 2.64 (m, 4H), 2.52 (m, 1H), 2.3 (m, 1H), 1.78 (m, 2H), 1.72 (m, 2H); MS (DCI/NH3) m/e 456 (M + H)+; Analysis calculated for C30H29N5SO4·3HCl·2H2O: C, 51.40; H, 5.18; N, 9.99; Found: C, 51.24; H, 5.23; N, 9.82.

Example 59 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 3E (0.13 g, 0.44 mmol) and the product from Example 57A (0.13 g, 0.45 mmol) were treated as described in Example 1F to give 0.045 g (17%) of the title compound: 1H NMR (300 MHz, CDCl3 (free base)) δ 9.09 (s, 1H), 8.12 (d, 1H), 7 (81, J = d Hz, 1H), 7.52 (dd, 1H), 7.11 (t, 1H), 6.51 (d, 1H), 6.42 (d, 1H), 4.52 (dd, 1H), 4.17 (m, 2H), 4.08 (m, 1H), 3.85 (m, 1H), 3.8 (s, 3H), 3.2 (m, 4H), 3.1 (m, 1H), 2.8 (m, 1H), 2.62 (m, 1H), 2.05 (m, 2H), 1.95 (m, 2H); MS (DCI/NH 3 ) m/e 562 (M + H) + .

Example 60 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 60A Methy 7-Amino-2-(3-pyridyl)thieno[2,3-b]pyrazine-6-carboxylate

A solution of methyl 7-amino-2-chloro-thieno[2,3- b]pyrazine-6-carboxylate prepared as described in Example 100 (0.468 g), diethyl(3-pyridyl)borane (0.293 g), Pd(dppf)Cl₂ (0.157 g), and K₂CO₃ (0.800 g) in degassed DMF (10 mL) was heated to 95°C for 1.5 hours, cooled in saturated NH₄Cl, the solid precipitate collected, washed with water, and dried. Purification by silica gel column chromatography gave 0.44 g (80%) of the title compound. 1H NMR (DMSO-d₆) δ 3.87 (3H, s), 7.25 (2H, br s), 7.6 (1H, dd), 8.75 (2H, m), 9.49 (1H, s), 9.58 (1H, m).

Example 60B 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 3E (0.24 g, 0.87 mmol) and the product from Example 60A (0.25 g, 0.87 mmol) were treated as described in Example 1F to give 0.14 g (29%) of the title compound: m.p. 235-240°; 1H NMR (300 MHz, CDCl3) δ 1.9 (4H, br m), 2.4 (4H, br m), 3.05 (1H, br m), 3.10 (3H, br m), 3.65 (1H, m), 3.74 (3H, s), 4.03 (1H, t), 4.19 (2H, t), 4.40 (1H, dd), 6.38 (1H, d), 6. 46 (1H, d), 7.07 (1H, t), 7.45 (1H, dd), 8.40 (1H, dt), 8.80 (1H, dd), 9.05 (1H, s), 9.36 (1H, d); MS (CI(NH3); m/e 557; Analysis calcd for C29H28N6O6S·1.75 HCl·2.75 H2O: C, 51.99; H, 5.30; N, 12.54; Cl, 9.26; Found: C, 51.78; H, 5.12; N, 12.20; Cl, 9.14.

Example 61 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 1E (0.18 g, 0.65 mmol) and the product from Example 60A (0.165 g, 0.58 mmol) were treated as described in Example 1F to give 0.18 g (56%) of the title compound: m.p. 190-205°; 1H NMR (300 MHz, CDCl3) δ 1.84 (4H, br n), 2.7-3.05 (6H, br m), 3.5 (4H, br m), 3.72 (3H, s), 3.87 (1H, br d), 4.10 (2H, br m), 4.22 (1H, br m), 6.20 (1H, br s), 6.34 (1H, br d), 6 .93 (1H, br t), 7.55 (1H, dd), 8.41 (1H, dt), 8.80 (1H, dd), 9.12 (1H, s), 9.34 (1H, d); MS (CI(NH3 )) m/e 557; Analysis calculated for C29H28N6O4S·1.7 HCl·2.5H2O: C, 52.48; H, 5.27; N, 12.66; Cl, 9.08; Found: C, 52.21; H, 5.11; N, 12.42; Cl, 8.80.

Example 62 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-furyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 62A Methyl 7-amino-2-(3-furyl)thieno[2,3-b]pyrazine-6-carboxylate

A solution of methyl 7-amino-2-chloro-thieno[2,3- b]pyrazine-6-carboxylate, prepared as described in Example 100 (0.300 g, 1.23 mmol), β-furanboronic acid (0.207 g, 1.85 mmol) was dissolved in 12 mL of anhydrous DMF. To this solution was added triethylamine (0.26 mL, 1.85 mmol, 1.5 equiv.), DPPP (153 mg, 0.37 mmol, 0.3 equiv.) and Pd(OAc)2 (83 mg, 0.37 mmol, 0.3 equiv.), followed by heating at 90° for 2 hours. The solvent was evaporated and the resulting residue was chromatographed (SiO2, 3:1 hexanes/ethyl acetate) to give the product as a slightly yellow solid (93 mg): 1H NMR (300 MHz, CDCl3) δ 7.02 (m, 1H), 7.57 (t, J = 3.0 Hz, 1H) 8.15 (m, 1H), 8.83 (s, 1H).

Example 62B 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-furyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 15 (0.097 g, 0.35 mmol), the product from Example 62A (0.073 g, 0.27 mmol), Et3N (0.1 mL, 0.68 mmol), and phosgene (0.7 mL of 1.93 M solution in toluene, 1.4 mmol) were treated as described in Example 1F to give 0.040 g (26%) of the title compound: mp 183-186°; 1H NMR (300 MHz, DMSOd6) δ. 1.61-1.80 (m, 5H), 2.70-2.81 (m, 1H), 1.81-2.96 (m, 2H), 3.12-3.33 (m, 2H), 3.37-3.53 (m, 1H), 3.77-3.93 (m, 1H), 3.80 (s, 3H), 3.93-4.0 2 (m, 2H), 4.02-4.15 (m, 2H), 6.51 (d, J = 8 Hz, 1H), 6.61 (d, J = 8 Hz, 1H), 7.14 (t, J = 8 Hz, 1H), 7.29 (d, J = 2 Hz, 1H), 7.92 (d; J = 2 Hz, 1H), 8.66 (s, 1H), 9.28 (s, 1H), 10.35 and 10.55 (bs and bs, 1H), 12.75 (bs, 1H); MS (CI(NH3)) m/e (M + H)+ at 546; analysis calcd for C28H27N5O5S·(HCl)2: C, 54.37; H, 4.73; N, 11.32; Found: C, 54.48; H, 5.03; N, 11.13.

Example 63 3-[2-((±)-cis-7-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 63A (±)-cis-7-Methoxy-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4- c]pyrrole

From 7-methoxycoumarin and N-methoxymethyl-Ntrimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C: 1H NMR (300 MHz, CDCl3), δ 1.92 (br s, 1H), 2.60 (m, 1H), 2.81 (m, 2H), 3.17 (q, 1H), 3.29 (dd, 1H), 3.40 (dd, 1H), 3.77 (s, 3H), 3.78 (t, 1H), 4.10 (dd, 1H), 6.43 (d, 1H), 6.52 (dd, 1H), 7.03 (d, 1H).

Example 63B 3-[2-((±)-cis-7-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 63A (0.41 g, 2.00 mmol), N-(2-chloroethyl)-N'-[3-[(2-methoxycarbonyl)benzothienyl]]urea (0.654 g, 2.00 mmol) prepared by the method described in Eur. J. Med. Chem., 28: 499-504 (1993), and ethyldiisopropylamine (0.44 mL, 2.5 mmol) were dissolved in DMSO (3 mL) and the reaction was heated to 100 °C for 3 h. The reaction was cooled to room temperature and 10 mL of water was added. The product was collected by filtration, recrystallized from 50% aqueous DMF and the resulting product treated with excess anhydrous HCl in ethanol. After addition of anhydrous ether, the title compound was collected to give 0.337 g: mp 204-7º; 1H NMR (300 MHz, DMSO-d₆) δ 2.75-2.9 (m, 1H), 2.9-3.2 (m, 2H), 3.4- 3.7 (m, 3H), 3.71 (s, 3H), 3.85-4.4 (m, 6H), 6.44 (dd, J = 1, 6.57,m Hz, 1H), 7.10 (d, 1H), 7.56 (m , 1H), 7.64 (m, 1H), 8.12 (b, 1H), 8.41 (d, 1H), 12.68 (br s, 1H); MS (DCI/NH 3 ) m/e 450 (M + H) + ; Analysis calculated for C24H24ClN3O4S: C, 59.32; H, 4.98; N, 8.65; Found: C, 59.06; H, 5.06; N, 8.45.

Example 64 3-[3-((±)-cis-7-methoxy-1,2,3,3a,4,9b-hexahvdro-[1]-benzopyrano[3,4-c]pyrrol-2--yl)propyl ]-[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 63A (0.41 g, 2.00 mmol), N-(3-chloropropyl)-N'-[3-[(2-methoxycarbonyl)benzothienyl]]urea (0.750 g, 2.20 mmol), prepared by the procedure described in Eur. J. Med Chem., 28:499-504 (1993), were treated as described in Example 63 to give 0.296 g of the title compound: mp 220-2°; 1H NMR (300 MHz, DMSO-d6) δ 1.95-2.1.5 (m, 2H), 2.7-3.0 (m, 3H), 3.1-3.7 (m, 4H), 3.70 (s, 3H), 3.86 (m, 1H), 3.91-4.17 (m, 4H), 6.42 (d, 1H), 6.55 (dd, J = 1, 7.56,t Hz, 1H) 7.64 (t, 1H), 8.11 (d, 1H), 8.41 (d, 1H), 12.59 (br s, 1H); MS (DCI/NH 3 ) m/e 464 (M + H) + ; Analysis calculated for C24 H26 CIN3 O4 S·1/2H2 O: C, 58.99; H, 5.34; N, 8.25; Found: C, 59.10; H, 5.25; N, 8.09.

Example 65 3-[2-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]-benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 65A (±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahvdro-[1]-benzopyrano[3,4- c]pyrrole

From 5-methoxycoumarin and N-methoxymethyl-N- trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C. 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H).

Example 65B 3-[2-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 65A (515 mg, 2.5 mmol), N-(2-chloroethyl)-N'-[3-[(2-methoxycarbonyl)benzothienyl]]urea (915 mg, 2.8 mmol) prepared by the procedure described in Eur. J. Med. Chem., 28:499-504 (1993), and ethyldiisopropylamine (1.0 mL) were treated as in Example 63B to give 0.200 g (18%) of the title compound: mp 224-228°; 1H NMR (300 MHz, CDCl3 (free base)) δ 2.40-2.53 (m, 2H), 2.56-2.68 (m, 1H), 2.81- 3.01 (m, 2H), 3.30 (dd, J = 7, 9 Hz, 1H), 3.43 (q, J = 8 Hz, 1H), 3.58 (t, J39 Hz, 1H), 3.72 (s, 3H ). H), 7.40 (t, J = 8 Hz, 1H), 7.54 (t, J = 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.24 (d, J = 8 Hz, 1H); MS (CI(NH3)) m/e (M + H)+ at 450; Analysis calculated for C24H23N3O4S·HCl·(H2O)0.5: C, 58.24; H, 5.09; N, 8.49; Found: C, 57.90; H, 4.76; N, 8.24.

Example 66 3-[3-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4-c]pyrrol-2-yl)propyl]- [1]benzthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product of Example 65A (500 mg, 2.4 mmol), N-(3-chloropropyl)-N'-[3-[(2-methoxycarbonyi)benzothienyl]]urea (1.7 g, 5.0 mmol), prepared by the method described in Eur. J. Med Chem., 28:499-504 (1993), and ethyldiisopropylamine (1.0 mL) were treated as described in Example 63B to give 300 mg (27%) of the title compound: mp 197-199°; 1H NMR (300 MHz, CD3 OD) δ. 2.08-2.20 (m, 2H), 2.87-3.01 (m, 1H), 3.14- 3.45 (m, 3H), 3.69 (q, J = 8 Hz, 1H), 3.77-3.87 (m, 1H), 3.85 (s, 3H), 3.92 (dd, J = 7, 12 Hz, 1H). ). (d, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1H); MS (CI(NH3)) m/e (M + H)+ at 464; Analysis calcd for C25H25N3O4S·HCl·CH3OH: C, 58.69; H, 5.68; N, 7.90; Found: C, 58.43; H, 5.23; N, 7.93.

Example 67 3-[2-((±)-cis-6-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 67A (±)-cis-6-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4- c]pyrrole

From 8-methoxycoumarin and N-methoxymethyl-Ntrimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C.

Example 67B 3-[2-(±)-cis-6-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl]- [1]-benzthieno[3,2- d]pyrimidine-2,4(1H, 3H)-dione hydrochloride

The product of Example 67A (600 mg, 2.9 mmol), N-(2-chloroethyl)-N'-[3-[(2-methoxycarbonyl)benzothienyl]]urea (1.2 g, 3.7 mmol) prepared by the method described in Eur. J. Med Chem., 28: 499-504 (1993), and ethyldiisopropylamine (1.5 mL) were treated as described in Example 63B to give 320 mg (24%) of the title compound: mp 251-254°; 1H NMR (300 MHz, CDCl3 (free base)) δ 2.43-2.52 (m, 2H), 2.67-2.79 (m, 1H), 2.90 (t, J = 7 Hz, 2H), 3.32-3.45 (m, 2H), 3.51 (t, J = 8 Hz, 1H), 3.82 (dd, J = 8, 11 Hz, 1H), 3.85 (s, 3 H), 4.13 (dd, J = 5, 9 Hz, 1H), 4.34 (t, 3 = 7 Hz, 2H), 6.65-6.72 (m, 2H), 6.81 (t, 3 = 8 Hz, 1H), 7.39 (t, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.24 (d, J = 8 Hz, 1H); MS (CI(NH3)) m/e (M + H)+ at 450; Analysis calcd for C24H23N3O4S·HCl: C, 59.32; H, 4.98; N, 8.65; Found: C, 59.18; H, 5.06; N, 8.54.

Example 68 3-[3-((±)-cis-6-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] -[1]benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 67A (500 mg, 2.4 mmol), N-(3- chloropropyl)-N'-[3-[(2-methoxycarbonyl)benzothienyl]]urea (1.7 g, 5.0 mmol) prepared by the procedure described in Eur. J. Med. Chem., 28: 499-504 (1993), and ethyldiisopropylamine (1.5 mL) were treated as described in Example 63B to give 610 mg (54%) of the title compound: mp 191-195°; 1H NMR (300 MHz, CDCl3 (free base)) δ 1.95-2.07 (m, 2H), 2.20-2.34 (m, 2H), 2.57-2.74(m, 3H), 3.21 (dd, J = 8, 9 Hz, 1H), 3.28-3.40 (m, 2H), 3.76 (dd, J = 8, 11 Hz, 1H), 3.83 (see , 3H), 4.10 (dd, J = 5, 11 Hz, 1H), 4.27 (t, J = 7 Hz, 2H), 6.61-6.70 (m, 2H), 6.80 (t, J = 8 Hz, 1H), 7.47 (dd, J = 1, 8 Hz, 1H), 7.56 (dd, J = 1, 8 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 8.26 (d, J = 8 Hz, 1H); MS (CI(NH3) m/e (M + H)+ at 464; Analysis calcd for C24H25N3O4S·HCl·(H2O)0.25: C, 59.52; H, 5.29; N, 8.33; Found: C, 59.17; H, 5.22; N, 8.24.

Example 69 3-[2-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl]-[1] Benzthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 69A (±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrole

From coumarin and N-methoxymethyl-N-trimethylsilylmethylbenzylamine in an analogous manner as described in Example 1A-C.

Example 69B 3-[2-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl]-[1] Benzthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 69A (540 mg, 2.8 mmol), N-(2-chloroethyl)-N'-[3-[(2-methoxycarbonyl)benzothienyl]]urea (0.89 g, 3.6 mmol) prepared by the procedure as described in Eur. J. Med. Chem., 28:499-504 (1993) and ethyldiisopropylamine (1.5 mL) were treated as described in Example 63B to give 410 mg (35%) of the title compound: mp 256-257°; 1H NMR (300 MHz, CD3CD) δ 3.00-3.13 (m, 1H), 3.23- 3.70 (m, 3H), 3.58 (t, J = 6 Hz, Hz), 3.72-3.80 (m, 1H), 3.87-4.20 (m, 2H), 4.03 (dd, J = 6, 12 Hz, 1H), 4.15 (dd, J = 4, 12 Hz, 1H), 4.41 (t, J = 6 Hz, 2H), 6.89 (dd, J = 1, 8 Hz, 1H), 6.96-7.02 (m, 1H), 7.18 (dt, J = 2.8 Hz, 1H), 7.25 (dd, J = 1.8 Hz, 1H), 7.58 (m, 1H), 7.60-7.67 (m, 1H), 7.99 (d, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1H); MS (CI(NH3) m/e (M + H)+ at 420; Analysis calcd for C23H21N3O3S·HCl: C, 60.59; H, 4.86; N, 9.22; Found: C, 60.38; H, 4.83; N, 9.14.

Example 70 3-[4-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-pyrido[2 ',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 70A (±)-cis-2-(4-aminobutyl)-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4-c]pyrrole

The product from Example 69A (1.0 g, 5.71 mmol) was treated as described in Examples 1D and 1E to give 1.1 g (98%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.4-1.8 (m, 6H), 2.20 (dd, 1H), 2.27 (t, 1H), 2.45 (m, 2H), 2.68-2.80 (m, 3H), 3.19 (dd, 1H), 3.37 (m, 2H), 3.75 (dd, 1H), 4.07 (dd, iH), 6.9 (m, 2H), 7.12 (m, 1H).

Example 70B 3-[4-((±)-cis-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-pyrido[2 ',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 70A (0.24 g, 1 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.30 g, 1.2 mmol) were treated as described in Example 1F to give 0.20 g (44%) of the title compound: mp 203-205°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.78 (d, 1H), 8.28 (d, 1H), 8.48 (bs, 1H), 7.52 (dd, 1H), 7.13 (m, 2H), 6.92 (m, 2H), 4.08 (m, 4H), 3.92 (m, 1H), 3.82 (m, 1H), 3.68 (q, 1H), 2 .98 (m, 3H), 2.73 (m, 2H), 1.78 (m, 4H); MS (DCI/NH 3 ) m/e 449 (M + H) + ; Analysis calculated for C24 H24 N4 O3 S·2HCl·H2 O: C, 53.43; H, 5.23; N, 10.39; Found: C, 53.24; H, 4.83; N, 10.25.

Example 71 3-[4-((±)-trans-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-pyrido[2 ',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 71A (±)-trans-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrole

Ethyl 2-methoxymethyl-cinnamate and N-methoxymethyl-Ntrimethylsilylmethyl-benzylamine were treated in an analogous manner as described in Examples 3A-C.

Example 71B (±)-trans-2-(4-aminobutyl)-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 71A (1.22 g, 6.97 mmol) was treated as described in Examples 1D and 1E to give 0.58 g (34%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.45-1.8 (m, 6H), 2.29 (m, 1H), 2.60-2.83 (m, 6H), 2.95 (m, 2H), 3.39 (dd, 1H), 4.12 (dd, 1H), 4.50 (dd, 1H), 6.83 (m, 2H), 6.91 (m, 1H), 7.13 (m, 1H).

Example 71C 3-[4-((±)-trans-1,2,3,3a,4,9b-Hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-pyrido[2 ',3':4,5]thieno[3.2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 71B (0.24 g, 1.0 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.35 g, 1.35 mmol) were treated as described in Example 1F to give 0.18 g (38%) of the title compound: mp >250°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.78 (d, 1H), 8.3 (bs, 1H), 8.29 (d, 1H), 7.53 (dd, 1H), 7.18 (t, 1H), 6.88 (m, 3H), 4.55dd, 1H), 4.12 (m, 3H), 4.05 (m, 1H), 3.51 (m, 1H), 3. 23 (m, 4H), 3.08 (m, 1H), 2.48 (m, 1H), 1.85 (m, 4H); MS (DCI/NH 3 ) m/e 452 (M + H) + ; Analysis calculated for C24H24N4O4S·HCl·0.5H2O: C, 58.35; H, 5.30; N, 11.34; Found: C, 58.43; H, 4.97; N, 11.34.

Example 72 3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 72A (±)-trans-2-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

Out of Ethyl 2-methoxy-6-methoxymethyl-cinnamate and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine, in an analogous manner as described in Examples 3A-C: 1H NMR, (300 MHz, CDCl₃) δ 2.07 (br s, 1H), 2.24 (m, 1H), 2.70 (m, 2H), 2.84 (t, 1H), 3.21 (dd, 1H), 3.77 (s, 3H), 3.83 (dd, 1H), 4.07 (dd, 1H), 4.53 (dd, 1H), 6.40 (d, 1H), 6.51 (d, 1H), 7.06 (t, 1H)

Example 72B (±)-trans-2-(4-aminobutyl)-9-methoxv-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 72A (1.2, 4.75 mmol) was treated as described in Examples 3D-E to give 1.0 g (64%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.40- 1.80 (m, 4H), 2.32 (m, 1H), 2.57 (t, 1H), 2.62-2.90 (m, 4H), 2.95 (t, 1H), 3.60 (m, 1H), 3.78 (s, 3H), 4.06 (dd, 1H), 4.45 (dd, 1H), 6.40 (d, 1H), 6.49 (d, 1H), 7.04 (t, 1H).

Example 72C 3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 72B (0.28 g, 1.0 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.27 g, 1.15 mmol) were treated as described in Example 1F to give 0.22 g (46%) of the title compound: mp >250°; 1H NMR (300 MHz, DMSO-d6 (free base)) δ. 1.42-1.54 (m, 2H), 1.60-1.72 (m, 2H), 2,042.18 (m, 1H), 2.25-2.89 (m, 4H), 3.10-3.48 (m, 3H), 3.68 (s, 3H), 3.95 (t, J = 7 Hz, 2H), 4.02 (d d, J = 10, 12 Hz, 1H), 4.39 (dd, J = 4, 10 Hz, 1H), 6.39 (dd, J = 1, 8 Hz, 1H), 6.44 (dd, J = 1, 8 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 7.64 (dd, J = 5, 8 Hz, 1H), 8.63 (dd, J = 1.8 Hz, 1H), 8.83 (dd, J = 1.5 Hz, 1H); MS (DCI/NH₃)) m/e 479 (M + H)⁺; Analysis calcd for C₂₅H₂₆N₄O₄S·2HCl·0.5H₂O: C, 53.57; H, 5.21; N, 10.00; Found: C, 53.49; H, 5.35; N, 9.88.

Example 73 3-[4-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 73A (±)-cis-2-(4-aminobutyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

From 5-methoxycoumarin and N-methoxymethyl-Ntrimethylsilylmethyl-benzylamine, in an analogous manner as described in Example 1A-C: 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H).

Example 73B (±)-cis-2-(4-aminobutyl)-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 73A (0.2, 1.0 mmol) was treated as described in Examples 1D-E to give 0.08 g (29%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.65- 1.80 (m, 4H), 2.19 (m, 1H), 2.25 (dd, 1H), 2.42 (m, 1H), 2.52 (t, 2H), 3.14 (dd, 1H), 3.18-3.30 (m, 2H), 3.79 (dd, 1H), 3.80 (s, 3H), 4.04 (dd, 1H), 6.46 (d, 1H), 6.54 (d, 1H), 7.07 (t, 1H).

Example 73C 3-[4-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 738 (0.28 g, 1.0 mmol) and methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.27 g, 1.15 mmol) were treated as described in Example 1F to give 0.20 g (42%) of the title compound: mp 198-200°; 1H NMR (300 MHz, CDCl3 (free base)) δ 1.56-1.99 (m, 2H), 1.71-1.83 (m, 2H), 2.26 (t, J = 9 Hz, 1HF), 2.34 (dd, J = 6, 10 Hz, 1H), 2.50-2.70 (m, 3H), 3.26 (dd, J = 7, 10 Hz, 1H), 3.43 (q, J = 8 Hz, 1H), 3.63 (t, J = 8 Hz, 1H), 3.79 (s, 3H), 3.76-3.86 (m, 1H), 4.01 (dd, J = 4.11 Hz, 1H), 4.11 (t, J = 7 Hz, 1H), 6.43 (d, J = 8 Hz, 1H), 6.49 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 7.49 (dd, 3 = 4.8 Hz, 1H), 8.23 (dd, J = 1.8 Hz, 1H), 8.78 (dd, J = 1.4 Hz, 1H); MS (DCI/NH₃) m/e 479 (M + H)⁺; Analysis calcd for C₂₅H₂₆N₄O₄S·2HCl·0.5H₂O: C, 53.57; H, 5.21; N, 10.00; Found: C, 53.41; H, 5.24; N, 9.88.

Example 74 3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (0.25 g, 1.0 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12:513 (1975) and the product from Example 72B (0.28 g, 1.0 mmol) were treated as described in Example 1F to give 0.18 g (38%) of the title compound: mp 193-195°; 1H NMR (300 MHz, DMSOd6 (free base)) δ 8.98 (d, 1H), 8.89 (d, 1H), 7.11 (t, 1H); 6.52 (d, 1H), 6.45 (d, 1H), 4.5 (dd, 1H), 4.2 (m, 1H), 4.1 (m, 1H), 3.92 (m, 2H), 3.73 (s, 3H), 3.0 (m, 1H), 2.6 (m, 5H), 2.3 (m, 1H), . 1.8 (m, 4H); MS (DCI/NH3) m/e 4809 (M + H)+; Analysis calcd for C24H25N5SO4·2HCl·2H2O: C, 48.98; H, 5.31; N, 11.90; Found: C, C48.48; H, 5.80; N, 11.94.

Example 75 3-[4-(±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]- pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 75A (±)-cis-2-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4- c]pyrrole

From 6-methoxycoumarin and N-methoxymethyl-Ntrimethylsilylmethyl-benzylamine, in an analogous manner as described in Examples 1A-C.

Example 75B (±)-cis-2-(4-aminobutyl)-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 75A (1.0 g, 4.0 mmol) was treated as described in Examples 1D-E to give 0.72 g (54%) of the title compound.

Example 75C 3-[4-((±))-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-thieno[2,3-b]pyridine-2-carboxylate (0.25 g, 1.07 mmol) and the product from Example 75B (0.26 g, 1.0 mmol) were treated as described in Example 1F to give 0.20 g (46%) of the title compound: mp 203-204°; 1H NMR (300 MHz, CDCl3 (free base)) 8.72 (dd, 1H), 8.6 (d, 1H), 8.38 (bs, 1H), 7.41 (dd, 1H), 6.82 (d, 1H), 6.71 (dd, 1H), 6.6 (d, 1H), 4.12 (m, 4H), 3 .98 (m, 2H), 3.78 (m, 1H), 3.73 (s, 3H), 3.12 (m, 2H), 3.05 (m, 1H), 2.92 (m, 1H), 2.85 (m, 1H), 1.82 (m, 4H); MS (DCI/NH 3 ) m/e 479 (M + H) + ; Analysis calculated for C₂₅H₂₆N₄O₄S·2HCl·0.5H₂O: C, 53.57; H, 5.22; N, 10.00; Found: C, 53.81; H, 5.06; N, 9.91.

Example 76 3-[4-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] - pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (0.25 g, 1.05 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12:513 (1975) and the product from Example 75B (0.28 g, 1.0 mmol) were treated as described in Example 1F to give 0.30 g (62%) of the title compound: mp 218-220°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.72 (m, 2H), 6.8 (d, 1H), 6.68 (dd, 1H), 6.61 (d, 1H), 4.12 (t, 2H), 4.0 (dd, 1H), 3.82 (m, 1H), 3.75 (s, 3H), 3.58 (m, 3H), 2.89 (m, 1H), 2. 79 (m, 2H), 2.52 (m, 2H), 1.75 (m, 4H); MS (DCI/NH 3 ) m/e 480 (M + H) + ; Analysis calculated for C24 H25 N5 O4 S·HCl·2H2 O: C, 52.22; H, 5.48; N, 12.69; Found: C, 52.68; H, 5.22; N, 12.63.

Example 77 3-[3-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] - pyrido[3',2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 77A (±)-cis-2-(3-aminopropyl)-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 75A (1.26 g, 6.14 mmol) was treated with 0.61 mL (7.36 mmol) of 3-bromopropionitrile followed by LiAlH4 and AlCl3 in an analogous manner as described in Examples 1D-E to give 0.85 g (52%) of the title compound.

Example 77B 3-[3-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)propyl] - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride.

Methyl 3-amino-thieno[2,3-b]ipyridine-2-carboxylate (0.25 g, 1.07 mmol) and the product from Example 78A (0.26 g, 1.0 mmol) were treated as described in Example 1F to give 0.23 g (50%) of the title compound: 1H NMR (300 MHz; CDCl3 (free base)) δ 8.64 (dd, 1H), 8.43 (dd, 1H), 8.45 (s, 1H), 7.32 (dd, 1H), 6.82 (dd, 1H), 6.7 (dd, 1H), 6.61 (d, 1H), 4.2 (m, 1H), 4.13 (t, 2H), 3.98 (m, .3H), 3.73 (m, 1H), 3.72 (s, 3H), 3.22 (m, 2H), 3.0 (m, 1H), 2.95 (d, 1H), 2.85 (m, 1H), 2.48 (m, 2H); MS (DCI/NH 3 ) m/e 465 (M + H) + ; Analysis calculated for C24H24N4O4S·HCl·H2O: C, 55.54; H, 5.24; N, 10.79; Found: C, 55.18; H, 4.98; N, 10.63.

Example 78 3-[2-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 78A (±)-cis-2-(2-aminoethyl)-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 75A (1.0 g, 4.88 mmol) was treated with 0.34 mL (5.36 mmol) of 2-chloroacetonitrile followed by LiAlH4 and AlCl3 in an analogous manner as described in Examples 1D-E to give 0.72 g (59%) of the title compound: 1H NMR (300 MH, CDCl3) δ 2.1 (br s, 2H), 2.25-2.45 (m, 2H), 2.52-2.65 (m, 2H), 2.72 (m, 1H), 2.83 (t, 2H), 3.17 (dd, 1H), 3.28-3.45 (m, 2H), 3.75 (dd, 1H), 3.77 (s, 3H), 4.01 (dd, 1H), 6.63 (dd, 1H), 6.68 (dd, 1H), 6.81 (d, 1H).

Example 78B 3-[2-((±)-cis-8-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)ethyl] - pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-thieno[2,3-b]pyridine-2-carboxylate (0.25 g, 1.07 mmol) and the product from Example 78A (0.25 g, 1.0 mmol) were treated as described in Example 1F to give 0.20 g (44%) of the title compound: 1H NMR (300 MHz, CDCl3 (free base)) δ 8.7 (dd, 1H), 8.48 (dd, 1H), 8.3 (bs, 1H), 7.32 (dd, 1H), 6.81 (dd, 1H), 6.7 (dd, 1H), 6.65 (dd, 1H), 4.5-4.7 (m, 3H), 4.0 (m, 3H), 3.76 (s, 3H), 3.4 (m, 2H), 3.1 (m, 2H), 2.9 (m, 2H); MS (DCI/NH 3 ) m/e 451 (M + H) + ; Analysis calculated for C23 H22 N4 O4 S·HCl·0.5H2 O: C, 55.70; H, 4.88; N, 11.30; Found: C, 55.61; H, 4.66; N, 11.19.

Example 79 3-[4-((±)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] -6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione hydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (0.28 g, 1.18 mmol) and the product from Example 73A (0.28 g, 1.0 mmol) were treated as described in Example 1F to give the intermediate urea which was treated with 1.5 mL of 1.0 M KOtBu in 20 mL of THF to give the title compound (0.19 g, 40%): mp 178-180° (dec); 1H NMR (300 MHz, CDCl3 (free base)) δ 7.44 (s, 1H), 7.06 (t, 1H), 6.48 (m, 2H), 6.42 (s, 1H), 4.06 (m, 3H), 4.0 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.83 (m, 1H), 3.8 (s, 3H), 3.48 (m, 1H), 3.2 (m, 1H), 2.58 (m, 3H), 2.3 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H); MS (DCI/NH 3 ) m/e 482 (M + H) + ; Analysis calculated for C26H31N3O6·HCl·2H2O: C, 56.37; H, 6.55; N, 7.58; Found: C, 56.61; H, 6.30; N, 7.47.

Example 80 3-[4-((±)-trans-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-6,7 -dimethoxy-quinazoline-2,4(1H,3H)-dione hydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (0.27 g, 1.15 M) and the product from Example 71B (0.25 g, 1.0 mmol) were treated as described in Example 1F to give the intermediate urea which was treated with 1.5 mL of 1.0 M KOtBu in 20 mL of THF to give the title compound (0.12 g, 26%): mp 182-184°; 1H NMR (300 MHz, CDCl3 (free base)) δ 7.41 (s, 1H), 7.18 (m, 1H), 6.88 (s, 1H), 6.86 (m, 2H), 6.71 (s, 1H), 4.55 (dd, 1H), 4.18 (t, 1H), 4.08 (t, 2H), 3.95 ts, 3H), 3.91 (s, 3H), 3.9 (m, 1H), 3.48 (m, 1H), 3.22 (m, 4H), 3.08 (m, 1H), 2.5 (m, 1H), 1.82 (m, 4H); MS (DCI/NH 3 ) m/e 452 (M + H) + ; Analysis calculated for C25H29N3O5·HCl·H2O: C, 59.34; H, 6.37; N, 8.32; Found: C, 59.12; H, 6.21; N, 7.82.

Example 81 3-[4-((±)-cis-1,2,3,3a,4,9b-hexahydro-[1]-benzopyranc[3,4-c]pyrrol-2-yl)butyl]-6,7 -dimethoxy-quinazoline-2,4(1H,3H)-dione hydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (0.27 g, 1.15 mmol) and the product from Example 70A (0.25 g, 1.0 mmol) were treated as described in Example 1F to give the intermediate urea which was treated with 1.5 mL of 1.0 M KOtBu in 20 mL of THF to give the title compound (0.18 g, 39%): 1H NMR (300 MHz, CDCl3 (free base)) δ 8.3 (b s, 1H), 7.46 (s, 1H), 7.08 (m, 2H), 6.88 (m, 2H), 6.39 (s, 1H), 4.08 (m, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.72 (m, 1H), 3.38 (m, 2H), 3 .21 (m, 1H), 2.72 (m, 1H), 2.52 (m, 2H), 2.28 (m, 2H), 1.75 (m, 2H), 1.62 (m, 2H); MS (DCI/NH 3 ) m/e 452 (M + H) + ; Analysis calculated for C25H29N3O5·HCl·2H2O: C, 57.19; H, 6.1; N, 8.00; Found: C, 56.63; H, 6.08; N, 7.51.

Example 82 3-[4-((±)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl] -6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione dihydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (0.28 g, 1.18 mmol) and the product from Example 72A (0.28 g, 1.0 mmol) were treated as described in Example 1F to give the intermediate urea, which was treated with 1.5 mL of 1.0 M KOtBu in 20 mL of THF to give the title compound (0.38 g, 79%): mp 189-191°; 1H NMR (300 MHz, CDCl3 (free base)) δ 7.44 (s, 1H), 7.05 (t, 1H), 6.49 (d, 1H), 6.41 (s, 1H), 6.39 (dd, 1H), 4.44 (dd, 1H), 4.1 (m, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.76 (s, 3H), 3. 6 (m, 1H), 2.99 (t, 1H), 2.78 (m, 4H), 2.58 (t, 1H), 2.3 (m, 1H), 1.75 (m, 2H), 1.65 (m, 2H); MS (DCI/NH 3 ) m/e 482 (M + H) + ; Analysis calculated for C26H31N3O6·2HCl·2H2O: C, 52.89; H, 6.32; N, 7.12; Found: C, 52.89; H, 5.99; N, 7.02.

Example 83 3-[3-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) propyl]-6,7-dimethoxy-quinazoline-2,4(1H, 3H)-dione hydrochloride Example 83A (±)-trans-N-benzyl-3-carboethoxy-4-(2-methoxy-6-methoxymethyl)phenyl-piperidine-2,5-dione

Ethyl 2-methoxy-6-methoxymethyl cinnamate (13.2 g, 59.7 mmol) was treated with ethyl N-benzylamidomalonate according to the procedure of Faruk and Martin, U.S. Patent No. 4,902,801, to give the title compound (8.34 g, 38%). 1H NMR (300 MHz, DMSO) δ 7.47-7.24 (m, 5H), 7.19 (dd, 1H), 6.71 (d, 1H), 6.68 (dd, 1H), 5.19 (dd, 2H), 4.88 (s, 2H), 4.70 (dt, 2H), 4.25 (dt, 1H), 3.90 (dq, 2H), 3.78 is, 3H), 3.41 (dd, 1H), 3.40 (s, 3H), 2.63 (dd, 1H), 0.87 (t, 3H). MS (DCI/NH 3 ) m/e 442 (M + H) + .

Example 83B (±)-trans-N-benzyl-3-chloromethyl-4-(2-hydroxy-6-methoxy)phenylpiperidine

To a solution of LiAlH4 (2.45 g, 64.6 mmol) in THF (250 mL) at 0 °C was added dropwise a solution of the product from Example 83A (9.50 g, 21.5 mmol) in THF (50 mL). The reaction was warmed to room temperature and then heated to reflux for 3 h. The reaction was cooled to 0 °C and quenched by the sequential addition of water (4 mL), 1 M NaOH (4 mL), and water (10 mL), and stirred for 1 h. The mixture was filtered through a pad of Celite and rinsed with EtOAc (500 mL). The organic layer was dried over MgSO4 and condensed in vacuo to give 8.0 g of a clear oil. The oil was taken up in methanol (250 mL) and concentrated 1-101 (15 mL) and stirred under reflux for 6 hours. The mixture was cooled, condensed in vacuo, and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The layers were separated and the aqueous layer extracted 2× with EtOAc. The combined organic layers were dried over MgSO4 and condensed in vacuo to give 7.0 g of a clear oil. To a solution of this oil in CCl4 (75 mL) and CH3CN (75 mL) was added triphenylphosphine (11.3 g, 43.1 mmol) and the solution was heated under reflux for 1 hour. The mixture was cooled and condensed in vacuo, and the residue was chromatographed on SiO2 using NH3. saturated 35% EtOAc/hexanes to give the title compound (5.30 g, 71%): 1H NMR (300 MHz, DMSO) δ 9.32 (br s, 1H), 7.35-7.22 (m, 5H), 6.96 (dd, 1H), 6.44 (br d, 2H), 3.72 (s, 3H), 3.51 (dd, 2H), 3.26 (m, 1H), 3.16 (m, 2H), 2.98 (dt, 1H), 2.85 (m, 2H), 2.24 (m, 1H), 1.93 (m, 1H), 1.78 (m, 1H), 1.39 (m, 1H). MS (DCI/NH3 ) m/e 346 (M + H)+ .

Example 83C (±)-trans-10-Methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

To To a solution of the product from Example 83B (5.30 g, 15.3 mmol) in THF (125 mL) was added a 1.0 M solution of potassium t-butoxide (16 mL) and the reaction was heated to reflux for 2 h. The reaction was cooled, poured into water, and extracted with 3X EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo to give 4.7 g of a clear oil. To a solution of the oil and 10% Pd on carbon (2 g) in MeOH (125 mL) was added ammonium formate (4.7 g, 75 mmol) and the reaction was heated to reflux for 2 h. The reaction mixture was cooled, filtered through a small pad of Celite, and rinsed with EtOAc (200 mL). The filtrate was dried over Na2SO4. dried and condensed in vacuo to give the title compound (3.01 g, 90%). 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.36 (d, 1H), 4.03 (dd, 1H), 3.72 (s, 3H), 3.55 (dd, 1H), 3.01 (m, 1H), 2.94 (dd, 1H), 2.83 (ddd, 1H), 2.62 (dt, 1H), 2.51 (dt, 1H), 2.29 (t, 1H), 1.64 (ddt, 1H), 1.05 (ddd, 1H). MS (DCI/NH 3 ) m/e 220 (M + H) + .

Example 83D (±)-trans-3-(2-cyanoethyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

A mixture of the product from Example 83C (340 mg, 1.55 mmol), 3-bromopropionitrile (193 μl, 2.33 mmol), and ethyldiisopropylamine (675 μl, 3.88 mmol) in acetonitrile (4 mL) was heated at reflux for 18 hours. The reaction was cooled and partitioned between EtOAc and 1 M NaOH. The organic layer was dried over MgSO4, the solvent was condensed in vacuo, and the crude product was chromatographed on SiO2 using EtOAc to give the title compound (0.335 g, 79%). 1H NMR (300 MHz, DMSO) δ 7.03 (dd, 1H), 6.49 (d, 1H), 6.38 (dd, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 3.04-2.86 (m, 3H), 2.65 (m, 4H), 2.41 (m, 1H), 2.16 (m , 1H), 1.81 (m, 2H), 1.18 (m, 1H). MS (DCI/NH 3 ) m/e 273 (M + H) + .

Example 83E (±)-trans-3-(3-aminopropyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 83D (355 mg, 1.30 mmol) was treated with 7.5 equivalents of LiAlH4 and 2.5 equivalents of AlCl3 by the procedure described in Example 13 to give the title compound (0.347 g, 96%). 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (dd, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.96 (m, 2H), 2.89 (m, 1H), 2.57 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.01 (dt, 1H), 1.77 (m, 1H), 1.66 (t, 1H), 1.51 (m, 2H), 1.17 (m, 1H). MS (DOI/NH 3 ) m/e 277 (M + H) + .

Example 83F 3-[3-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) propyl]-6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione hydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (258 mg, 1.09 mmol) and the product from Example 83E (250 mg, 0.905 mmol) were treated as described in Example 1F to give the title compound (347 mg, 71%): mp 230 °C. 1H NMR (300 MHz, DMSO) δ 11.35 (s, 1H), 10.61 (br s, 1H), 7.31 (s, 1H), 7.08 (t, 1H), 6.74 (s, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.13 (dd, 1H), 3.98 (m, .2H), 3.84 (s, 3 H), 3.81 (s, 3H), 3.75 (s, 3H), 3.63 (m, 1H), 3.58 (m, 2H), 3.10 (m, 4H), 2.84 (m, 1H), 2.76 (m, 1H), 2.24 (m, 1H), 2.19 (m, 2H), 1.57 (m, 1H). MS (DCI/NH3) m/e 482 (M + H)'. Analysis calcd for C26H31N3O6·1.6HCl: C, 57.85; H, 6.09; N, 7.78. Found: C, 57.73; H, 5.99; N, 7.57.

Example 84 3-[3-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) propyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-thieno[2,3-b]pyridine-2-carboxylate (254 mg, 1.09 mmol) and the product from Example 83E (250 mg, 0.904 mmol) were treated as described in Example 1F to give the title compound (281 mg, 59%). mp > 300 °C. 1H NMR (300 MHz, DMSO) ? 12.80 (s, 1H), 10.44 (br s, 1H), 8.83 (d, 18), 8.78 (d, 1H), 7.67 (dd, 1H), 7.09 (t, 1H), 6.53 (d, 1H), 6.42 (d, 1H), 4.14 (dd, 1H), 4.03 (m, 2H), 3.76 (s, 3H), 3.64 (m, 1H), 3.59 (m, 2H), 3.24-3.02 (m, 4H) , 2.85 (m, 1H), 2.76 (m, 1H), 2.22 (m, 1H), 2.13 (m, 2H), 1.53 (m, 1H). MS (DCI/NH₃) m/e 479 (M + H)⁺. Analysis calculated for C₂₅H₂₆N₄O₄S·1.35HCl: C, 56.89; H, 5.22; N, 10.62 . Found: C, 57.03; H, 5.06; N, 10.45.

Example 85 3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 85A (±)-trans-3-(3-cyanopropyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 83C (380 mg, 1.73 mmol) was treated with 1.5 equivalents of 4-bromobutyronitrile and 2.5 equivalents of ethyldiisopropylamine by the procedure described in Example 83D to give the title compound (0.38 g, 71%). 1H NMR (300 MHz, DM50) δ 7.03 (dd, 1H), 6.49 (d, 1H), 6.38 (dd, 1H), 4.09 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.93 (m, 3H), 2.39 (m, 2H), 2.08 (m, 1H), 1.74 (m, 3H), 1.30 (m, 1H). MS (DCI/NH 3 ) m/e 287 (M + H) + .

Example 85B (±)-trans-3-(4-aminobutyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 85A (380 mg, 1.33 mmol) was treated with 7.5 equivalents of LiAlH₄ and 2.5 equivalents of AlCl₃ by the procedure described in Example 83E to give the To give title compound (0.358 g, 93%). 1 H NMR (300 MHz, DMSO) ? 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.97 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.38 (m, 1H), 2.29 (m, 2H), 2.01 (dt, 1H), 1.78 (m, 1H), 1.67 (t, 1H), 1.46 (m, 2H), 1.34 (m, 28), 1.18 (m, 1H). MS (DCI/NH3 ) m/e 291 (M + H)+ .

Example 85C 3-[4-((±)-trans-10-methoxy-1,3,3,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-thieno[2,3-b]pyridine-2-carboxylate (0.194 g, 1.09 mmol) and the product from Example 85B (0.200 g, 0.69 mmol) were treated as described in Example 1F to give the title compound (0.245 g, 59%): mp 251-4 °C; 1H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.76 (br s, 1H), 8.77 (d, 1H), 8.74 (dd, 1H), 7.61 (dd, 1H), 7.04 (t, 1H), 6.50 (d, 1H), 6.38 (dd, 1H), 4.12 (dd, 1H), 3.92 (t, 2H), 3.71 (s, 3H), 3.62 (t, 1H), 3.52 (m, 2H), 3.06 (m, 4H), 2.78 (m, 2H), 2.25 (m, 1H), 1.76 (m, 2H), 1.64 (m, 2H), 1.54 (m, 1H). MS (DCI/NH3) m/e 493 (M + H)+. Analysis calcd for C26H28N4O4S·2HCl: C, 51.88; H, 5.19; N, 9.31. Found: C, 52.24; H, 5.52; N, 9.32.

Example 86 3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione hydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (0.196 g, 0.83 mmol) and the product from Example 85B (0.200 g, 0.69 mmol) were treated as described in Example 1F to give the title compound (0.140 g, 37%): mp 220 °C. 1H NMR (300 MHz, DMSO) δ 11.27 (s, 1H), 10.54 (br s, 1H), 7.25 (s, 1H), 7.04 (t, 1H), 6.68 (s, 1H), 6.50 (d, 1H), 6.39 (d, 1H), 4.12 (dd, 1H), 3.87 (t, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.62 (t, 1H), 3.62 (m, 2H), 3.06 (m, 4H), 2.76 (m, 2H), 2.21 (m, 1H), 1.71 (m, 2H), 1.59 (m, 2H), 1.51 (m , 1H). MS (DCI/NH 3 ) m/e 496 (M + H) + . Analysis calculated for C27 H33 N3 O6 ·1.4HCl: C, 59.37; H, 6.35; N, 7.69. Found: C, 59.36; H, 6.56; N, 7.57.

Example 87 3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-[1]-benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-benzo[b]thiophene-2-carboxylate (0.143 g, 58 mmol) and the product from Example 85B (0.14 g, 0.48 mmol) were treated as described in Example 1F to give the title compound (0.121 g, 48%): mp >305 °C. 1H NMR (300 MHz, DMSO) δ 12.56 (s, 1H), 10.44 (br s, 1H), 8.37 (d, 1H), 8.07 (d, 1H), 7.60 (t, 1H), 7.52 (t, 1H), 7.04 (t, 1H), 6.50 (d, 1H), 6.38 (d, 1H), 4.12 (dd, 1 8), 3.93 (t, 2H), 3.71 (s, 3H), 3.62 (t, 1H), 3.53 (m, 2H), 3.06 (m, 4H), 2.77 (m, 2H), 2.20 (in, 1H), 1.76 (m, 2H), 1.65 (m, 2H), 1.52 (m, 1H). MS (DCI/NH3) m/e 492 (M + H)+. Analysis calcd for C27H29N3O4S HCl: C, 61.41; H, 5.73; N, 7.96. Found: C, 61.16; H, 5.48; N, 7.79.

Example 88 3-[4-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.135 g, 0.58 mmol) and the product from Example 85B (0.14 g, 0.48 mmol) were treated as described in Example 1F to give the title compound (0.15 g, 54%): mp >325 °C. 1H NMR (300 MHz, DMSO) δ. 12.68 (s, 1H), 10.65 (br s, 1H), 8.85 (d, 1H), 8.66 (dd, 1H), 7.68 (dd, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (dd, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.58 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.28 (m, 1H), 1.79 (m, 2H), 1.69 (m, 2H), 1.58 (m, 1H). MS (DCI/NH3) m/e 493 (M + H)+. Analysis calculated for C26H28N4O4S·2HCl·0.5H2O: C, 54.36; H, 5.44; N, 9.75. Found: C, 54.25; H, 5.59; N, 9.68.

Example 89 3-[3-((±)-trans-10-methoxy-1,3,4,4a,5,10b--hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl )propyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H, 3H)-dione hydrochloride

Methyl 3-amino-benzo[b]thiophene-2-carboxylate (0.177 g, 0.72 mmol) and the product from Example 83E (0.165 g, 0.60 mmol) were treated as described in Example 1F to give the title compound (0.187 g, 61%): mp > 300 °C. 1H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 10.41 (br s, 1H), 8.43 (d, 1H), 8.13 (d, 1H), 7.66 (t, 1H), 7.57 (t, 1H), 7.08 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.14 (dd, 1 H), 4.02 (m, 2H), 3.76 (s, 3H), 3.63 (m, 1H), 3.59 (m, 2H), 3.22-3.03 (m, 4H), 2.86 (m, 1H), 2.77 (m, 1H), 2.22 (m, 1H), 2.13 (m, 2H), 1.54 (m, 1H). MS (DCI/NH₃) m/e 478 (M + H)⁺. Analysis calcd for C₂₆H₂₇N₃O₄S·1.0HCl: C, 60.75; H, 5.49; N, 8.17. Found: C, 60.48; H, 5.50; N, 8.02.

Example 90 3-[2-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) ethyl]-[1]benzothieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride Example 90A (±)-trans-3-(cyanomethyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

To a solution of the product from Example 83C (0.80 g, 3.66 mmol) and K2CO3 (1.21 g, 8.8 mmol) in acetone (20 mL) and water (2 mL) was added chloroacetonitrile (278 μL, 4.4 mmol) and the solution was stirred at reflux for 18 h. The reaction was cooled and poured into brine, the solution was extracted with 3 x EtOAc and the combined Organic extracts were dried over MgSO4. The solvent was condensed in vacuo and the crude product was chromatographed on SiO2 using 30% EtOAc/hexanes to give the title compound (0.55 g, 58%). 1H NMR (300 MHz, DMSO) δ 7.04 (dd, 1H), 6.50 (d, 1H), 6.38 (d, 1H), 4.08 (dd, 1H), 3.74 (s, 3H), 3.68 (t, 1H), 2.91 (m, 2H), 2.39 (ddt, 2H), 2.03 (m, 1H), 1.83 (m, 1H), 1.24 (m, 1H). MS (DCI/NH 3 ) m/e 259 (M + H) + .

Example 90B (±)-trans-3-(2-aminoethyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

To a solution of LiAlH4 (285 mg, 7.50 mmol) in Et2 O (25 mL) was added dropwise a solution of AlCl3 (333 mg, 2.50 mmol) in Ebt (10 mL) and the reaction was stirred for 10 min. A solution of the product from Example 90A (259 mg, 1.00 mmol) in THF (10 mL) was added via syringe and the reaction was stirred for 1 h. The reaction was cooled to 0 °C and quenched by the sequential addition of water (2 mL), 1 M NaOH (4 mL) and water (4 mL) and then stirred for 1 h. The mixture was filtered through a pad of celite and rinsed with EtOAc (100 mL) and CHCl3 (100 mL). The organic layer was rinsed with brine, dried over Na2SO4 and condensed in vacuo to give the title compound (0.225 g, 86%). 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.49 (d, 1H), 6.38 (dd, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.61 (t, 1H), 2.93 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.07 (dt, 1H), 1.79 (m, 1H), 1.62 (m, 2H), 1.19 (m, 1H). MS (DCI/NH 3 ) m/e 263 (M + H) + .

Example 90C 3-[2-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-c]pyrido-3-yl)ethyl ]-[1]-benzthieno[3,2- d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Methyl 3-amino-benzo[b]thiophene-2-carboxylate (0.158 g, 0.64 mmol) and the product from Example 90B (0.140 g, 0.53 mmol) were treated as described in Example 1F to give the title compound (0.143 g, 54%): mp > 305ºC. ¹H NMR (300 MHz, DMSO) &delta ; 12.74 (s, 1H), 10.34 (s, 1H), 8.42 (d, 1H), 8.12 (d, 1H), 7.67 (dd, 1H), 7.58 (dd, 1H), 7.09 (dd, 1H), 6.55 (d, 1H), 6.43 (d, 1H), 4.34 (m, 2H), 4.15 (dd, 1H), 3.85 (m, 2H), 3.76 (s, 3H), 3.71 (t, 1H), 3, 42 (m, 2H), 3.15 (m, 2H), 2.98 (m, 1H), 2.82 (m, 1H), 2.20 (m, 1H), 1.54 (m, 1H). MS (DCI/NH₃) m/e 464 (M + H)⁺. Analysis calculated for C₂₅H₂₅N₃O₄S·HCl: C, 60.05; H, 5.24; N, 8.40. Found: C, 59.68; H, 5.21; N, 8.25.

Example 91 3-[2-((±)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) ethyl]-6,7-dimethoxy-quinazoline-2,4(1H,3H)-dione hydrochloride

Methyl 2-amino-4,5-dimethoxybenzoate (0.152 g, 0.64 mmol) and the product from Example 90B (0.140 g, 0.53 mmol) were treated as described in Example 1F to give the title compound (0.060 g, 22%): mp 291-2 °C. 1H NMR (300 MHz, DMSO) δ 11.44 (s, 1H), 10.09 (s, 1H), 7.30 (s, 1H), 7.09 (dd, 1H), 6.72 (s, 1H), 6.55 (d, 1H), 6.42 (d, 1H), 4.30 (m, 2H), 4.14 (dd, 1H), 3.85 (m, 2H). ). MS (DCI/NH3) m/e 468 (M + H)+. Analysis calcd for C24H29N3O6·1.25HCl: C, 58.52; H, 5.94; N, 8.19. Found: C, 58.79; H, 6.00; N, 8.01.

Example 92 3-[3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 92A (4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine-4-menthylcarbamate and (4aR,10bS )- trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine-4-menthylcarbamate

To a solution of the product from Example 83C (3.16 g, 14.41 mmol) and ethyldiisopropylamine (5.02 mL, 28.8 mmol) in CH2Cl2 (200 mL) at 0 °C was added (+)-menthyl chloroformate (3.71 mL, 17.3 mmol). The reaction was warmed to 23 °C and stirred for 3 h. The reaction was then poured into 1 M NaOH, the layers separated, and the aqueous layer extracted with 3 x Et2O. The combined organic layers were dried over MgSO4, the solvent was condensed in vacuo, and the crude product was chromatographed on SiO2. using 10% EtOAc/hexanes to give a mixture of diastereomers (5.30 g, 92%). The 1:1 mixture of the two diastereomers was separated on a preparatory chiral HLPC column. 1H NMR (300 MHz, DMSO) δ 7.04 (dd, 1H), 6.50 (d, 1H), 6.39 (d, 1H), 4.46 (m, 1H), 4.10 (m, 3H), 3.74 (s, 3H), 3.61 (t, 1H), 2.94 (m, 2H), 2.63 (m, 2H), 1.89 (m, 2H), 1 .83 (m, 1H), 1.62 (m, 3H), 1.41 (m, 1H), 1.36 (m, 1H), 1.00 (m, 4H), 0.87 (m, 6H), 0.72 (m, 3H). MS (DCI/NH 3 ) m/e 402 (M + H) + .

Example 92B (4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

To a solution of (4aS, 10bR), the slower moving diastereomer from Example 92A (2.38 g, 5.93 mmol) in THF (125 mL) at 0 °C was added a solution of 1.6 M n-BuLi (15.0 mL, 24.0 mmol) dropwise and the reaction was stirred for 15 min. The reaction was quenched with 1 M NaOH, poured into brine, and extracted with 3 x EtOAc and 2 x CH 2 Cl 2 . The combined extracts were dried over Na 2 SO 4 , the solvent was condensed in vacuo, and the crude product was chromatographed on SiO 2 using NH 3 . saturated 5% MeOH/CH2Cl2 to give the title compound (1.07 g, 82%); 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.36 (d, 1H), 4.03 (dd, 1H), 3.72 (s, 3H), 3.55 (dd, 1H), 3.01 (m, 1H), 2.94 (dd, 1H), 2.83 (ddd, 1H), 2.62 (dt, 1H), 2.51 (dt, 1H), 2.29 (t, 1H), 1.64 (ddt, 1H), 1.05 (ddd, 1H). MS (DCI/NH 3 ) m/e 220 (M + H) + .

Example 92C (4aS,10bR)-trans-3-(3-aminopropyl)-10-methoxy-1,3,4,4a,5,10bhexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 92B was treated as described in Examples 83D and 83E to give the title compound; 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (dd, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.96 (m, 2H), 2.89 (m, 1H), 2.57 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.01 (dt, 1H), 1.77 (m, 1H), 1.66 (t, 1H), 1.51 (m, 2H), 1.17 (m, 1H). MS (DCI/NH 3 ) m/e 277 (M + H) + .

Example 92D 3-[3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- vl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (107 mg, 0.456 mmol) and the product from Example 92C (105 mg, 0.380 mmol) were treated as described in Example 1F to give the title compound (135 mg, 64%): mp 235 °C; 1H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.66 (br s, 1H), 8.86 (d, 1H), 8.68 (dd, 1H), 7.68 (dd, 1H), 7.09 (t, 1H), 6.53 (d, 1H), 6.41 (dd, 1H), 4.14 (dd, 1H), 4.00 (m, 2H), 3.76 (s, 3H), 3.63 (m, 1H), 3.59 (m, 2H), 3.21-3.03 (m, 4H), 2.86 (m, 1H), 2.76 (m, 1H), 2.28 (m, 1H), 2.12 (m, 2H), 1.56 (m, 1H). MS (DCI/NH3) m/e 479 (M + H)+. Analysis calcd for Cz5H26N4O4S·2.0HCl·0.5H2O: C, 53.57; H, 5.22; N, 10.00. Found: C, 53.35; H, 5.05; N, 9.92. [α]D25.0ºC = -79.4ºC.

Example 93 3-[3-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopytano[3,4-c]pyrido-3- yl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 93A (4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrldine

To a solution of (4aR,10bS), the faster running diastereomer from Example 92A (2.27 g, 5.74 mmol) in THF (125 mL) at 0 °C was added a solution of 1.6 M n-BuLi (15.0 mL, 24.0 mmol) dropwise and the reaction was stirred for 15 min. The reaction was quenched with 1 M NaOH, poured into brine and extracted with 3 x EtOAc and 2 x CH2Cl2. The combined extracts were dried over Na2SO4, the solvent was condensed in vacuo and the crude product was chromatographed on SiO2 using NH3. saturated 5% MeOH/CH2Cl2 to give the title compound (0.96 g, 80%); 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.36 (d, 1H), 4.03 (dd, 1H), 3.72 (s, 3H), 3.55 (dd, 1H), 3.01 (m, 1H), 2.94 (dd, 1H), 2.83 (ddd, 1H), 2.62 (dt, 1H), 2.51 (dt, 1H), 2.29 (t, 1H), 1.64 (ddt, 1H), 1.05 (ddd, 1H). MS (DCT/NH 3 ) m/e 220 (M + H) + .

Example 93B (4aR,10bS)-trans-3-(3-aminopropyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 93A was treated as described in Example 83D and 8% to give the title compound; 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.96 (m, 2H), 2.89 (m, 1H), 2.57 (m, 2H), 2.39 (m, 1H), 2.33 (m, 2H), 2.01 (dt, 1H), 1.77 (m, 1H), 1.66 (t, 1H), 1.51 (m, 2H), 1.17 (m, 1H). MS (DCI/NH 3 ) m/e 277 (M + H) + .

Example 93C 3-[3-((4aR, 10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.116 g, 0.495 mmol) and the product from Example 93B (0.114 g, 0.413 mmol) were treated as described in Example 1F to give the title compound (0.091 g, 39%): mp 235 °C. 1H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 10.66 (br s, 1H), 8.86 (d, 1H), 8.68 (dd, 1H), 7.68 (dd, 1H), 7.09 (t, 1H), 6.53 (d, 1H), 6.41 (dd, 1H), 4.14 (dd, 1H), 4.00 (m, 2H), 3.76 (s, 3H), 3.63 (m, 1H), 3.59 (m, 2H), 3.21-3.03 (m, 4H), 2.86 (m, 1H), 2.76 (m, 1H), 2.28 (m, 1H), 2.12 (m, 2H), 1.56 (m, 1H). MS (DCI/NH3) m/e 479 (M + H)+. Analysis calcd for C25H26N4O4S·2.0HCl·H2O: C, 52.73; H, 5.31; N, 9.84. Found: C, 52.59; H, 5.04; N, 9.75. [α]D25.0ºC = +77.7º.

Example 94 3-[4-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-pyrido[2'3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 94A (4aR,10bS)-trans-3-(4-aminobutyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 93A was treated as described in Examples 85A and 85B to give the title compound; 1H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.97 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.38 (m, 1H), 2.29 (m, 2H), 2.01 (dt, 1H), 1.78 (m, 1H), 1.67 (t, 1H), 1.46 (m, 2H), 1 .34 (m, 2H), 1.18 (m, 1H). MS (DCI/NH3 ) m/e 291 (M + H)+ .

Example 94B 3-[4-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrane[3,2-c]oyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.087 g, 0.372 mmol) and the product from Example 94A (0.090 g, 0.310 mmol) were treated as described in Example 1F to give the title compound (0.080 g, 43%): 1H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.65 (br s, 1H), 8.85 (d, 1H), 8.66 (dd, 1H), 7.68 (dd, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (dd, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.58 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.28 (m, 1H), 1.79 (m, 2H), 1.69 (m, 2H), 1.58 (m, 1H). MS (001/NH3) m/e 493 (M + H)+. Analysis calculated for C26H28N4OqS·2.0HCl·2.0H2O: C, 51.92; H, 5.70; N, 9.31. Found: C, 52.27; H, 5.56; N, 9.24. [α]D25.0ºC = +83.2º.

Example 95 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride Example 95A (4aS,10bR)-trans-3-(4-aminobutyl)-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyridine

The product from Example 92B was treated as described in Examples 85A and 85B to give the title compound; ¹H NMR (300 MHz, DMSO) δ 7.02 (dd, 1H), 6.48 (d, 1H), 6.37 (d, 1H), 4.08 (dd, 1H), 3.73 (s, 3H), 3.62 (t, 1H), 2.97 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.38 (m, 1H), 2.29 (m, 2 H), 2.01 (dt, 1H), 1.78 (m, 1H), 1.67 (t, 1H), 1.46 (m, 2H), 1.34 (m, 2H), 1.18 (m, 1H). MS (DCI/NH3 ) m/e 291 (M + H)+ .

Example 95B 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

Methyl 3-amino-thieno[3,2-b]pyridine-2-carboxylate (0.097 g, 0.413 mmol) and the product from Example 95A (0.100 g, 0.344 mmol) were treated as described in Example 1F to give the title compound (0.114 g, 55%): 1H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 10.65 (br s, 1H), 8.85 (d, 1H), 8.66 (dd, 1H), 7.68 (dd, 18), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (dd, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.58 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.28 (m, 1H), 1.79 (m, 2H), 1.69 (m, 2H), 1.58 (m, 1H). MS (DCI/NH3) m/e 493(M + H)+. Analysis calculated for C26H28N4O4S·2.0HCl·2.0H2O: C, 51.92; H, 5.70; N,9.31. Found: C, 51.48; H, 5.62; N, 9.05. [α]D25.0ºC = -82.4º.

Example 96 3-[4-((4aR,10bS)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-chloropyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 100 (0.106 g, 0.372 mmol) and the product from Example 94A (0.090 g, 0.310 mmol) were treated as described in Example 1F to give the title compound (0.020 g, 11%): mp 253-4 °C. 1H NMR (300 MHz, DMSO) δ 12.92 (s, 18), 10.45 (br s, 1H), 9.02 (s, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1H), 3.57 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.25 (m, 1H), 1.78 (m, 2H), 1.69 (m, 2H), 1.56 (m, 1H). MS (DCI/NH 3 ) m/e 528 (M + H) + . Analysis calculated for C25 H26 N5 O4 SCl·2.0HCl·0.5H2 O: C, 49.23; H, 4.79; N, 11.48. Found: C, 48.95; H, 4.77; N, 11.22. [α]D25.0ºC = +57.6º.

Example 97 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-chloro-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 10C (0.189 g, 0.667 mmol) and the product from Example 95A (0.176 g, 0.606 mmol) were treated as described in Example 1F to give the title compound (0.192 g, 55%): mp 254-5 °C. 1H NMR (300 MHz, DMSO) δ 12.92 (s, 1H), 10.45 (br s, 1H), 9.02 (s, 1H), 7.09 (t, 1H), 6.54 (d, 1H), 6.42 (d, 1H), 4.17 (dd, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.67 (t, 1 H), 3.57 (m, 2H), 3.11 (m, 4H), 2.81 (m, 2H), 2.25 (m, 1H), 1.78 (m, 2H), 1.69 (m, 2H), 1.56 (m, 1H). MS (DCI/NH 3 ) m/e 528 (M + H) + . Analysis calculated for C25H26N4O4S·2.0HCl·3.0H2O: C, 45.84; H, 5.23; N, 10.69. Found: C, 45.47; H, 5.03; N, 10.51. [α]D25.0ºC = -58.4º.

Example 98 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl-butyl]-8-methoxy-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 7A (0.24 g, 1.00 mmol) and the product from Example 95A (0.276 g, 1.00 mmol) were treated as described in Example 1F to give the title compound (0.30 g, 57%): mp >250°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.04 (d, 1H), 7.03 (t, 1H), 6.98 (d, 1H), 6.46 (d, 1H), 6.41 (d, 1H), 4.12 (t, 2H), 4.08 (dd, 1H), 4.04 (s, 3H), 3.79 (s, 3H), 3.67 (m, 1H), 3.08 (m, 1H), 2.98 (m, 2H), 2.42 (m, 3H), 2.13 (m, 1H), 2.02 (m, 1H), 1.76 (m, 3H), 1.62 (m, 2H), 1.38 (m, 1H); MS (DCI/NH 3 ) m/e 523 (M + H) + ; Analysis calculated for C27 H30 N4 O5 S·HCl·0.5H2 O: C, 57.09; H, 5.68; N, 9.86; Found: C, 57.01; H, 5.43; N, 9.64.

Example 99 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-8-methoxypyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product of Example 31A (0.167 g, 0.70 mmol) and the product of Example 95A (0.195 g, 0.70 mmol) were treated as described in Example 1F to give the title compound (0.29 g, 78%): mp 220-224°; 1H NMR (300 MHz, CDCl3 (free base)) δ 8.39 (s, TH), 7.04 (t, TH), 6.46 (d, 1H), 6.41 (d, 1H), 4.11 (m, 3H), 4.08 (s, 3H), 3.79 (s, 3H), 3.67 (t, 1H), 3.08 (m, 1H), 2.98 (m, 2H), 2.42 ( m, 3H), 2.15 (m, 1H), 2.0 (m, 1H), 1.78 (m, 3H), 1.6 (m, 2H), 1.4 (m, 1H); MS (DCI/NH 3 ) m/e 524 (M + H) + ; Analysis calculated for C26H29N5O5S·HCl·2H2O: C, 52.39; H, 5.75; N, 11.75; Found: C, 52.59; H, 5.70; N, 11.65.

Example 100 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 9B (0.16 g, 0.56 mmol) and the product from Example 95A (0.154 g, 0.56 mmol) were treated as described in Example 1F to give the title compound (0.17 g, 53%): mp >250°; 1H NMR (300 MHz, CDCl3 (free base)) δ. 9.16 (s, 1H), 8.08 (m, 2H), 7.59 (m, 3H), 7.02 (t, 1H), 6.42 (d, TH), 6.38 (d, 1H), 4.18 (m, 2H), 3.93 (dd, 1H), 3.77 (s, 3H), 3.6 (t, 1H), 3.18 (m, 1H), 3.07 (m, 1H), 2.93 (m, 1H), 2.5 (m, 2H), 2.41 (m, 1H), 2.16 (m, 1H), 1.97 (m, 1H), 1.8 (m, 3H), 1.76 (m, 2H), 1.18 (m, 1H); MS (DCI/NH3) m/e 570(M + H)+; Analysis calcd for C31H31N5SO4·HCl·1.5H2O: C, 58.81; H, 5.57; N, 11.06; Found: C, 58.69; H, 5.52; N, 11.03.

Example 101 3-[4-(4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzogyrano[3,4-c]pyrido-3-yl )butyl]-8-phenylpyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione dihydrochloride

The product from Example 95B (0.145 g, 0.50 mmol) and the product from Example 52A (0.15 g, 0.53 mmol) were treated as described in Example 1F to give 0.230 g (80%) of the title compound: m.p. >255º; 1H NMR (300 MHz, CDCl3 (free base)) δ 1.35 (dd, J = 3, 12 Hz, 1H), 1.58-1.72 (m, 2H), 1.72-1.87 (m, 3H), 1.91-2.05 (m, 1H), 2.12 (dd, J = 3, 12 Hz, 1H), 2.36-2.50 (m, 3H), 2.89-3 .02 (m, 2H), 3.04-3.13 (m, 1H), 3.63 (dd, J = 10, 11 Hz, 1H), 3.77 (s, 3H), 4.03 (dd, J = 3, 10 Hz, 1H), 4.18 (t, J = 7 Hz, 2H), 6.39 (dd, J = 1, 8 Hz, 1H), 6.45 (dd, J = 1, 8 Hz, 1H), 7.03 (t, J = 8 Hz, 1H), 7.45-7.56 (m, 3H), 7.93 (d, J = 9 Hz, 1H), 8.05- 8.11 (m, 2H), 8.27 (d, J = 9 Hz, 1H); MS (CI(NH3)) m/e (M + H)+ at 569; Analysis calcd for C32H32N4O4S·(HCl)2·(H2O)0.5: C, 59.07; H, 5.42; N, 8.61; Found: C, 59.04; H, 5.53; N, 8.35.

Example 102 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-7-chloronyrido[3',2':4,5']thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 95B (0.290 g, 1.0 mmol) and methyl 3-amino-6-chloro-thieno[2,3-b]pyridine-2-carboxylate (0.242 g, 1.00 mmol) were treated as described in Example 1F to give 0.375 g (66%) of the title compound: mp 236º(d); 1H NMR (300 MHz, DMSO-d6) δ. 1.4-1.6 (m, 2H), 1.6-1.85 (n, 4H), 2.04- 2.24 (m, 2H), 2.7-3.6 (m, 6H), 3.66 (t, 2H), 3.77 (s, 3H), 3.95 (t, 2H), 4.15 (m, 1H), 6.41 (d, 1H). ), 6.52 (d, 1H); 7.07 (t, 1H), 7.78 (d, 1H), 8.77 (d, 1H); MS (DCI/NH3) m/e 527 (529 (M + H)+); Analysis calcd for C26H28Cl2N4O4S·1.25H2O: C, 53.29; H, 5.25; N, 9.56; Cl, 12.10; Found: C, 53.26; H, 5.28; N, 9.27; Cl, 11.82.

Example 103 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro- 2H-[1]-benzopyrano[3,4-c]pyrido-3- yl)butyl]-7-methoxypyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

The product from Example 95B (0.290 g, 1.0 mmol) and methyl 3-amino-methoxy-thieno[2,3-b]pyridine-2-carboxylate (0.238 g, 1.00 mmol) were treated as described in Example 1F to give 0.315 g (56%) of the title compound: mp 224º(d); 1H NMR (300 MHz, DMSO-d6) δ 1.4-1.6 (m, 2H), 1.6-1.85 (m, 4H), 2.04- 2.15 (m, 2H), 2.7-3.6 (m, 6H), 3.67 (t, 2H), 3.77 (s, 3H), 3.96 (m, 2H), 3.98 (s, 3H), 4.15 (m, 1H). ), 6.41 (d, 1H), 6.54 (d, 1H), 7.07 (d, 1H), 7.08 (t, 1H), 8.58 (d, 1H); MS (DCI/NH 3 ) m/e 523 (M + H) + ; Analysis calculated for C27H31ClN4O5S·1.4H2O: C, 54.65; H, 5.78; N, 9.44; Cl, 7.47; Found: C, 54.52; H, 5.91; N, 9.31; Cl, 7.55.

Example 104 3-[4-(-cis-7-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione Example 104A 3-[4-(-cis-7-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

A solution of 7-hydroxy-5-methoxycoumarin (300 mg, 1.6 mmol), prepared as described in Monatsh. Chem., 1333, (1988), in dry DMF (10 mL) was treated with a 60% dispersion of sodium hydride (70 mg, 1.7 mmol) for 1 hour, treated with benzyl bromide (0.37 mL, 3.1 mmol) and stirred for 1 hour. The mixture was diluted with diethyl ether (100 mL), washed with water, brine, dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel using dichloromethane and then 25:1 dichloromethane:ethyl acetate gave 420 mg (95%) of the intermediate benzylated derivative.

A solution of 7-benzyloxy-5-methoxycoumarin (0.42 g, 1.5 mmol) in dichloromethane (5 mL) at 0 °C was treated with trifluoroacetic acid (0.15 mL of a 1 M solution in dichloromethane), treated dropwise with a solution of N-methoxymethyl-N-trimethylsilylmethylbenzylamine (750 mg, 3.0 mmol) in dichloromethane (5 mL) and stirred for 1 hour at ambient temperature. The mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4), filtered and concentrated. The residue was dissolved in THF (5 mL), added dropwise to a stirred suspension of lithium aluminum hydride (115 mg, 3.0 mmol) in THF (10 mL), stirred for 1 h, and treated with sodium sulfate decahydrate (5 g) in portions. The mixture was diluted with ethyl acetate, filtered, and concentrated. Purification on silica gel using 2:1 ethyl acetate:hexane afforded 620 mg (96%) of the intermediate diol.

A solution of the diol (0.60 g, 1.4 mmol) in a mixture of acetonitrile (16 mL) and carbon tetrachloride (4 mL) was treated with triphenylphosphine (0.73 g, 2.8 mmol), heated to reflux for 10 min, cooled to ambient temperature, and concentrated. Purification on silica gel using 2:1 diethyl ether:hexane saturated with ammonia afforded 530 mg (92%) of the intermediate chlorophenol. The chlorophenol (SBO mg, 1.8 mmol) dissolved in THF (30 mL) was treated with potassium tert-butoxide (3 mL of a 1 M in THF solution), stirred for 1 h, concentrated, treated with dichloromethane (100 mL), washed with water (25 mL), dried (MgSO4), filtered and concentrated to give 0.40 g (76%) of the ring-closed product. A suspension of this product (0.40 g, 0.96 mmol) and 10% palladium on carbon (0.070 g) in methanol (20 mL) was stirred under a.

hydrogen atmosphere for 16 hours. The atmosphere was replaced with nitrogen, the palladium on carbon was removed by filtration and the mixture was concentrated. Purification of the residue on silica gel using 8:1:1 ethyl acetate:water:formic acid gave an impure product which was repurified on silica gel using 40% ethanol in dichloromethane saturated with ammonia to give 0.060 g (28%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 2.25-2.39 (m, 1H), 2.34 (dd, 1H), 2.48-2.55 (m, 1H), 2.89 (q, 1H), 3.10 (dd, 1H), 3.33-3.42 (m, 1H), 3.49 (t, 1H), 3.70 (s, 3H), 3.98 (dd, 1H), p. 86 (d, J = 1 Hz, 2H), 5.99 (d, J = 1 Hz, 2H), 9.23 (bs, 1H); MS (DCI/NH3 ) m/e 222 (M + HN4)+ .

Example 104B 3-[4-(-cis-7-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

A solution of the product from Example 104A (60 mg, 0.27 mmol) in DMF (1.5 mL) was treated with 4-bromobutyronitrile (0.030 mL, 0.30 mmol) and sodium bicarbonate (25 mg, 0.30 mmol), heated to 70 °C for 3 hours, and concentrated. Purification using silica gel with 2% ethanol in dichloromethane saturated with ammonia provided 70 mg (90%) of the intermediate nitrile.

A suspension of lithium aluminum hydride (70 mg, 1.8 mmol) in a mixture of diethyl ether (3 mL) and THF (3 mL) was treated with aluminum chloride (81 mg, 0.61 mmol) in diethyl ether (3 mL), stirred for 1 hour, treated with the nitrile (70 mg, 0.24 mmol), stirred for 2 hours, treated with water (0.080 mL), treated with 4 M sodium hydroxide (0.080 mL), treated with water (0.24 mL), stirred for 15 minutes, and concentrated. Purification of the residue using silica gel with 12:5:3 ethyl acetate:formic acid:water gave the formic acid salt of the primary amine product.

A solution of the product from Example 9B (82 mg, 0.29 mmol) in THF (5 mL) was treated with sodium bicarbonate (100 mg, 1.2 mmol), treated with phosgene (3.75 mL of a 1.93 M solution in toluene), stirred for 1 hour, concentrated, dried at 60 °C under strong vacuum for 1 hour, and cooled to ambient temperature. The residue was treated with a suspension of the primary amine intermediate in DMF (4.5 mL), stirred for 1 hour, heated to 150 °C under nitrogen for 30 minutes, and concentrated. Purification of the residue using silica gel with 10% and then 20% ethanol in dichloromethane saturated with ammonia afforded 60 mg (43%) of the title compound: 1H NMR (300 MHz, DMSO-d₆) δ 1.42-1.54 (m, 2H), 1.58-1.71 (m, 2H), 2.14-2.25 (m, 2H), 2.38-2.51 (m, 2K), 2.99 (t, 1H), 3.10 (q, 1H), 3.17-3.26 (m, 1H), 3.39-3.49 (m, 1H), 3.62 (t, 1H), 3.69 (s, 3H), 3.90-4.00 (m, 3H), 5.84 (d, J = 1 Hz, 2H), 5.98 (d, J = 1 Hz, 2H), 7.53-7.65 (m, 3H), 8.40-8.47 (m, 2H), 9.24 (bs, 1H), 9.51.(s, 1H), 12.60 (bs, 1H); MS (ESI) m/e 572 (M + H)+; 570 (M - H)⁻.

Example 105 3-[4-((3aR,9bR)-cis-6-hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole- 2-yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione Example 105A (3aR,9bR)-cis-6-Bromo-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The HCl salt of the product from Example 1C (1 g, 4.14 mmol) was dissolved in formic acid, cooled to 0 °C and Br 2 (0.68 g, 4.25 mmol) was added. The reaction was stirred at 0 °C for 1 h, then the solvent was evaporated and the product was partitioned in 1 N NaOH/CH 2 Cl 2 . The organic extracts were dried and concentrated. The resulting product was purified by column chromatography on silica gel, eluting with 5% EtOH/CH 2 Cl 2 saturated with NH 4 OH, to give 0.45 g (38%) of the title compound. 1H NMR (300 MHz, CDCl 3 ) δ 2.58 (m, 1H), 2.64 (m, 1H), 2.84 (dd, 1H), 3.24 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.80 (m, 1H), 3.81 (s, 3H), 6.38 (d, 1H), 7.32 (d, 1H); MS (DCI (NH 3 )) m/e 284 (M + H) + .

Example 105B (3aR,9bR)-cis 6-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole

The product from Example 105A (0.45 g, 1.6 mmol) was dissolved in CH2Cl2 and di-t-butyl dicarbonate (0.69 g, 3.2 mmol) was added. After the reaction mixture was stirred at room temperature for 1 h, it was evaporated and the residue was purified by column chromatography on silica gel, eluting with 1:1 hexane:EtOAc to give the t-BOC-protected product (0.42 g). To the solution of the t-BOC-protected product (0.15 g, 0.46 mmol) in THF and cooled to -78 °C, 0.22 mL of 2.5M n-BuLi solution in hexane was added. The reaction mixture was stirred at -78°C for 1 hour and triisopropyl borate (0.11 g, 0.59 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours. Then acetic acid (0.55 mmol) was added to the reaction mixture followed by the addition of H2O5 (0.78 mmol). The reaction mixture was stirred at room temperature for 16 hours, then quenched in NH4Cl solution and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to give the t-BOC protected title compound (0.8 g). To the solution of t-BOC protected title compound (0.12 g, 0.37 mmol) in CH2Cl2 was added CF3COOH and the reaction was stirred overnight. The solvent was evaporated and the residue was purified by column chromatography eluting with 2% EtOH/CD2Cl to give 0.08 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 2.67 (m, 1H), 2.82 (dd, 1H), 2.97 (dd, 1H), 3.39 (m, 2H), 3.62 (dd, 1H), 3.78 (m, 1H), 3.77 (s, 3H), 3.81 (m, 1H), 4.18 (dd, 1H), 6.37 (d, 1H), 6.74 (d, 1H);

Example 105C

(3aR,9bR)-cis-2-(3-cyanopropyl)-6-hydroxy-9-methoxy- 1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole To the product from Example 105B (0.075 g, 0.34 mmol) in DMF (2 mL) was added NaHCO3 (0.032 g, 0.38 mmol) and 4-bromobutyronitrile (0.056 g, 0.38 mmol). The reaction mixture was heated to 90 °C for 3 h and evaporated. The residue was purified by column chromatography on silica gel eluting with 2% EtOH/CH2Cl2/saturated with ammonia to give 0.086 g (88%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.82 (m, 2H), 2.26 (m, 2H), 2.43 (t, 2H), 2.6 (m, 3H), 3.39 (m, 2H), 3.75 (s, 3H), 3.87 (m, 1H), 4.12 (dd, 1H), 5.15 (d, 1H), 6.73 (d, 1H)

Example 105D (3aR,9bR)-cis-2-(4-aminobutyl)-6-hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c] pyrrole

The product from Example 105C (0.084 g, 0.3 mmol) in THF was added to the solution of LiAlH₄ (0.085 g, 2.3 mmol) in THF and AlCl₄ (0.1 g, 0.75 mmol) in ether. The reaction mixture was stirred at room temperature for 3 hours to give, after a strict work-up, 0.075 g (88%) of the title compound. ¹H NMR (300 MHz, CDCl₃) d 1.48-1.7 (m, 4H), 2.38 (m, 1H), 2.43 (m, 3H), 2.73 (m, 2H), 3.06 (m, 1H), 3.39 (m, 2H), 3.47 (m, 1H), 3.77 (s, 3H), 3 .84-33.95 (m, 2H), 4.05 (m, 1H), 6.38 (d, 1H), 6.73 (d, 1H).

Example 105E 3-[4-((3aR,9bR)-cis-6-Hydroxv 9-Methoxy-1,2,3,3a4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl )butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

The product from Example 105D (0.084 g, 0.3 mmol) and the product from Example 9B (0.087 g, 0.3 mmol) were treated as described in Example 1F to give 0.03 g (17%) of the title compound. HNMR (500 MHz, CDCl3) δ 1.72 (m, 2H), 1.81 (m, 1H), 2.45 (m, 1H), 2.57 (m, 1H), 2.73 (m, 3H), 3.32 (m, 1H), 3.5 (m, 1H) 3.7 (s, 3H), 3.86 (m, 1H); 4.06 (m, 1H), 4.15 (m, 2H), 6.28 (d, 1H), 6.67 (d, 1H), 7.55 (m, 3H), 8.08 (m, 2H), 9.12 (s, 1H); MS (ESI)m/e 572 (M + H)+s

Example 106 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(2-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

To the solution of the product from Example 16 (0.075 g, 0.136 mmol) in DMF (2 mL) was added Pd(dppf)Cl2 (0.03 g, 0.034 mmol), 2-(benzyloxy)benzenbroic acid (0.033 g, 0.145 mmol) and triethylamine (0.05 mL). The reaction mixture was heated to 90 °C for 3 h. Then it was diluted with water and the precipitate formed was filtered off. The filtrate was extracted with EtOAc, dried over MgSO4 and evaporated. The residue was chromatographed on silica gel, eluting with 5% ethanol/CH2Cl2 saturated with ammonia to give 0.05 g (55%) of an oil. To the solution of this product (0.08 g, 0.12 mmol) in CH3OH (2 mL) was added ammonium formate (0.07 g) and Pd/C (0.07 g). The reaction mixture was heated to reflux for 2 hours, then it was filtered and the evaporated residue was chromatographed on silica gel eluting with 10% EtOH/CH2Cl2/saturated with NH4OH to give 0.022 g (32%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.8 (m, 4H), 2.5 (m, 1H), 2.58 (m, 1H), 2.8 (m, 3H), 3.58 (m, 2H), 3.78 (s, 3H), 3.82 (m, 2H), 3.88 (dd, 1H), 4.28 (m, 2H), 6.45 (m, 2H), 7.06 (m, 3H), 7.42 (t, 1H), 7.92 (dd, 1H), 9.33 (s, 1H); MS (ESI) m/e 572 (M + H)+.

Example 107 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-(3-hydroxyphenyl)pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H, 3H)-dione

The product of Example 16 (0.07 g, 0.105 mmol) and 3-(benzyloxy)benzeneboric acid were treated as described in Example 106 to give 0.03 g (43%) of the benzyl-protected product. To the solution of this product (0.015 g, 0.02 mmol) in CH3COOH were added a few drops of H2SO4 and the solution was heated to reflux for 0.5 h. The reaction mixture was cooled, neutralized and extracted with CH2Cl2/CH2CH to give 0.003 g (26%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 1.81 (m, 2H), 1.98 (m, 2H), 2.25 (m, 1H), 2.62 (m, 1H), 2.85 (m, 1H), 3.03 (m, 2H), 3.25 (m, 2H), 3.8 (s, 3H), 3.82 (m, 2H), 4.0 (m, 2H), 4.42 (m, 1H), 6.52 (m, 3H), 7.12 (m, 3H), 7.42 (t, 1H), 7.85 (s, 1H), 9.11 (s, 1H); MS(ESI)m/e 572 (M + H)+.

Example 108 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-berizopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(4-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

The product of Example 16 (0.07 g, 0.105 mmol) and 4-(methoxymethyloxy)phenylboronic acid (0.02 g, 0.11 mmol) prepared by the procedure described in Tetr.Lett., 31, 27, (1990) were treated as described in Example 106 to give 0.029 g (45%) of MOM-protected product. To the solution of this product (0.11 g, 0.17 mmol) in CH2OH/THF was added 2N HCl (0.2 mL) and the reaction mixture was heated to reflux for 1 h. The reaction was evaporated and partitioned into NaHCO2 solution and CH2Cl2/CH3OH to give 0.005 g (51%) of the title compound. 1 H NMR (500 MHz, CDCl3 ) ? 1.81 (m, 2H), 1.98 (m, 2H), 2.25 (m, 1H), 2.65 (m, 1H), 2.88 (m, 1H), 3.08 (m, 2H), 3.22 (m, 2H), 3.65 (m, 1H), 3.73 (m, 1H), 3.82 (s, 3H), 3. 9 (m, 1H), 4.25 (m, 1H), 4.42 (m, 1H), 6.52 (m, 2H), 7.38 (m, 2H), 7.49 (m, 1H), 7.9 (t, 1H), 8.09 (d, 1H), 9.12 (s, 1H); MS(ESI)m/e 572 (M + H)+.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the compounds described. Variations and changes which are obvious to one skilled in the art are within the scope and nature of the invention as defined in the appended claims.

Claims (47)

1. A compound according to formula I: or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms and R₃ is elected from the group consisting of, wherein G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, V and V' are independently selected from the group of nitrogen and methine, and U is a ring fused to the adjacent ring and selected from the group consisting of (a) an unsubstituted or substituted five-membered ring having five carbon atoms; (b) an unsubstituted or substituted five-membered ring having four carbon atoms and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (c) an unsubstituted or substituted five-membered ring having three carbon atoms and two heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; (d) a substituted or unsubstituted six-membered ring having six carbon atoms; (e) a substituted or unsubstituted six-membered ring having 5 carbon atoms and one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; (f) a substituted or unsubstituted six-membered ring having 4 carbon atoms and two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and (g) a substituted or unsubstituted six-membered ring having three carbon atoms and three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The five-membered rings forming U may contain 0, 1 or 2 double bonds. The six-membered rings forming U may contain 0, 1, 2 or 3 double bonds. The rings (a)-(g) from the group forming U may be mono- or di-substituted with substituents independently selected from the group consisting of alkyl, alkoxy, cyano, nitro, carboxy, alkoxycarbonyl of two to eight carbon atoms, halogen, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 2. A compound according to claim 1, wherein the five and six membered ring comprising U contains at least 1 double bond. 3. A compound according to claim 1 having formula II: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, P', Q, S' and T are independently selected from the group consisting of nitrogen and methine, provided that no more than two of P', Q, S' and T can be nitrogen and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic or a pharmaceutically acceptable salt, ester or prodrug thereof. 4. A compound according to claim 1 having the formula III: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently are selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, P' and T are nitrogen, Q and S' are methine, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 5. A compound according to claim 1 having the formula IV: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2 , W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, P' is nitrogen, Q, S' and T are methine and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 6. A compound according to claim 1 having the formula V: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2 , W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, Q is nitrogen, P', S' and T are methine, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic, or a pharmaceutically acceptable salt, ester or prodrug thereof. 7. A compound according to claim 1 having the formula VI: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent and when Y' is oxygen or sulfur, G' is absent, S' is nitrogen, P', Q and T are methine and R₄ and R₅ are alkylene. are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 8. A compound according to claim 1 having the formula VII: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2 , W is alkylene of from 2 to 10 carbons, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent, and when Y' is oxygen or sulfur, G' is absent, T is nitrogen, P', Q and S' are methine and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 9. A compound according to claim 1 having the formula VIII: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, A is methylene, n is 1 or 2, W is alkylene of from 2 to 10 carbon atoms, G and G' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, alkylsulfonyl and aminoalkyl, Y and Y' are independently selected from the group consisting of oxygen, nitrogen and sulfur, provided that when Y is oxygen or sulfur, G is absent and when Y' is oxygen or sulfur, G' is absent, P', Q, S' and T are methine, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 10. A compound according to claim 1 having the formula I, selected from the group consisting of: 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloro-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4[1H]-dior, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloro-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine,-2,4(1H,3H)-diori 3-[4-((3aR,96R)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrol-2-yl) butyl]-8-methoxy-pyrido[2',3':4.5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxy-pyrazino[2',3':4.5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxy-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloro-pyrido[3',2':4,5]thieno[3,2-d]pyrimididine-2,4(1H,3H)-dione, 3-(4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole-2-yDbutyl] -8-chloro-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrol-2-yl) butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(18,3H)-dione, 3-(4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxy-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-(4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxy-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloro-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-(4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-isopropoxy-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-(4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenyl-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione. 3-[3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((4aS,1ObR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-8-methoxy-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((4a5,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-8-methoxy-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((4aS,10bR)-trans-10-Mechoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yI)butyl]-8-phenyl-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,38)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrane[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-furyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione and 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt, ester or prodrug thereof. 11. A compound according to claim 1 having the formula IX: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 1, W is alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, P', Q, S' are methine, T is nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 12. A compound of formula IX according to claim 11, wherein the compound is selected from the group of: 3-[4-((3aR,9bR)-cis-9-merhoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole-2-y1) butyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-biethoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrol-2-yl) butyl]-pyzzdo[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxy-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloro-pyrido[2',3':4.5]thieno[3,2-d]pyrimidim-2,4(1H,3H)-dione, 3-[4((3aS,9bR)-trans-9-mechoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-isopropoxy-pyrido[2',3':4,5]thieno[3,2d]pyrimidine-2,4(1H,3H)-dione, and 3-[4-((3aS,9bR)-trans-9-Methoxv-1,2,3,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole-2- yl)butyl]-8-phenyl-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt, ester or prodrug thereof. 13. A compound according to claim 1 having the formula X: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 2, W is alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, P', Q and S' are methine, T is nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 14. A compound having the formula X according to claim 13 selected from the group consisting of: 3-[3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yt)propyl]-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl) butyl]-8-merhoxy-pyrido[2',3':4,5]thieno[3,2-d]pyridine-2,4(1H,3H)-dione, 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-8-methoxy-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, and 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-8-phenyl-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt, ester or prodrug thereof. 15. A compound according to claim 1 having the formula XI: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, and alkoxy, A is methylene, n is 2, W is alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, Q and S' are methine, P' and T are nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl, and heterocyclic; or a pharmaceutically acceptable salt, ester, or prodrug thereof. 16. A compound of formula XI according to claim 15, wherein the compound is selected from the group consisting of: 3-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4-c]pyrido-3-yl)butyl ]-8-methoxy-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, and 3-[4-((4aS,10bR)-trans-10-methoxy-1,3,4,4a,5,10b-hexahydro-2H-[1]-benzopyrano[3,4- c]pyrido-3- yl)butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt, ester or prodrug thereof. 17. A compound according to claim 1 having the formula XII: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 1, W is alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, Q and S' are methine, P' and T are nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 18. A compound of formula XII according to claim 17, wherein the compound is selected from the group consisting of: 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloro-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H,)-dione 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-chloro-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxy-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-e]pyrrol-2-yl) butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 3-(4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-methoxy-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine2,4(1H,3H)-dionex 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrido[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) buryi]-8-(3-pyridyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dior, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrol-2-yl) buryl]-8-(3-furyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) buryl]-8-(3-thienyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H,3H)-dione 3-[4-(-cis-7-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl ]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrirnidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-6-Hydroxy-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole- 2-yl)butyl]-8-phenyl-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione. 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(2-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine 2,4(1H,3H)-dione 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(3-hydroxyphenyl)-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, and 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-8-(4-hydroxyphenyl)-pyrazino[2',3':4,5]chieno[3,2-d]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt, ester or prodrug thereof. 19. A compound according to claim 1 having the formula XIII: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, A is methylene, n is 1, W is alkylene of 2 to 10 carbon atoms, G is hydrogen, G' is absent, Y is nitrogen, Y' is sulfur, Q, S' and T are methine, P' is nitrogen, and R₄ and R₅ are independently selected from hydrogen, alkyl, alkoxy, halogen, hydroxy, amino, cycloalkyl, aryl and heterocyclic; or a pharmaceutically acceptable salt, ester or prodrug thereof. 20. A compound of formula XIII according to claim 19, wherein the compound is selected from the group consisting of: 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl) butyl]-7-methoxy-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole-2-yi) butyl]-7-chloro-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole-2-yI) butyl]-1-methoxy-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dionef, and 3-[4-((3aS,9bR)-trans-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzapyrano[3,4-c]pyrrol-2-yl) butyl]-7-chloro-pyrido[3',2':4.5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt, ester or prodrug thereof. 21. A compound according to claim 1 having the formula XIV: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen and alkoxy, Y is nitrogen, G is hydrogen, Y' is sulfur, P' and T are nitrogen, and Q is methine, and S' is carbon; or a pharmaceutically acceptable salt, ester or prodrug thereof. 22. A compound of formula XIV according to claim 21, wherein the compound is 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9bhexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione; or a pharmaceutically acceptable salt, ester or prodrug thereof. 23. A compound of formula XIV according to claim 22, wherein the compound is 3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9bhexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenylpyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride. 24. A compound according to formula XVI: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, and n is 1 or 0; or a pharmaceutically acceptable salt thereof. 25. A compound according to formula XVII: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, m is from 2 to 10, and n is 1 or 0, or a pharmaceutically acceptable salt thereof. 26. A compound of claim 24 having the formula XIX: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino, and aminoalkyl, and n is 1 or 0, or a pharmaceutically acceptable salt thereof. 27. A compound according to claim 26, wherein the absolute stereochemistry is 3aR and 9bR. 28. A compound according to claim 25, having the formula XX: wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, halogen, nitro, amino and aminoalkyl, m is from 2 to 10, and n is 1 or 0; or a pharmaceutically acceptable salt thereof. 29. A compound according to claim 28, wherein the absolute stereochemistry is 3aR and 9bR. 30. A compound according to formula XXI: wherein U, Y', G' are as defined in formulas I-XIV, and R is alkyl; or a pharmaceutically acceptable salt thereof. 31. A compound according to formula XXII: wherein U, Y', G' are as defined in formulas I-XIV, and R is alkyl; or a pharmaceutically acceptable salt thereof. 32. A compound according to formula XXIII: wherein U, Y', G' and m are as defined in formulas I-XIV, and R is alkyl; or a pharmaceutically acceptable salt, thereof. 33. A compound according to formula XXIV: where Rz is alkyl. 34. A compound according to formula XXV: where Rz is alkyl. 35. A compound according to formula XXVI: wherein X is halogen and R is selected from alkyl and arylalkyl. 36. A compound according to formula XXVII: 37. A compound according to formula XXVIII: 38. A compound according to formula XXIX: 39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in association with a pharmaceutically acceptable carrier. 40. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 22 in association with a pharmaceutically acceptable carrier. 41. A compound according to claim 1 or claim 22 for use as a medicament. 42. Use of a compound according to claim 1 or according to claim 22 for the manufacture of a medicament for antagonizing α-1 adrenoreceptors in a host mammal. 43. Use of a compound according to claim 1 or according to claim 22 for the manufacture of a medicament for the treatment of benign prostatic hyperplasia (BPH) in a host mammal. 44. Use of a compound according to claim 1 or according to claim 22 for the manufacture of a medicament for the treatment of bladder outlet obstruction (B00) in a host mammal. 45. Use of a compound according to claim 1 or claim 22 for the manufacture of a medicament for treating a neurogenic bladder in a host mammal. 46. Use of a compound according to claim 1 or according to claim 22 for the manufacture of a medicament for treating uterine smooth muscle contraction in a host mammal. 47. A process for preparing a compound of formula or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R₁, R₂, A, n, W, Y, G, Y', G', P, Q, S, T, R₄ and R₅ are as previously defined comprising the step of: a) react a compound with the formula where Ra is aminoalkyl, b) with a compound of the formula where R is alkyl.